Method of Using Composition Comprising Mixed Metal Compounds and Xanthan Gum

ABSTRACT

The present invention provides a composition comprising (i) a mixed metal compound containing at least one trivalent metal selected from iron (III) and aluminium and at least one divalent metal selected from of magnesium, iron, zinc, calcium, lanthanum and cerium, (ii) xanthan gum (iii) at least one of (a) polyvinyl pyrrolidone (b) locust bean gum (c) methyl cellulose wherein the composition has been irradiated with ionising radiation in an amount of at least 4kGy.

The present invention relates to liquid formulation containingwater-insoluble inorganic mixed metal compounds. The present inventionfurther relates to methods of manufacture of the liquids and their usein unit and multiple dose forms for oral administration.

BACKGROUND OF THE INVENTION Liquid Dosage Forms

Liquid dosage forms of insoluble compounds can provide a useful means ofadministration for subjects who have difficulty swallowing. Inparticular in the field of pharmaceuticals ease of administration mayalso help ensure optimal patient compliance. Additionally liquid formallows for a continuously variable dose quantity to be administered.

Many liquid doses forms of insoluble compounds are known from the art.For example, Altacite Plus Suspension (Peckforton PharmaceuticalsLimited) is sold as an antacid for the symptomatic relief of dyspepsia,flatulence and abdominal hyperacidity, gastritis, peptic ulceration,heartburn especially when associated with hiatus hernia, or heartburnduring pregnancy. One of the active ingredients is ‘hydrotalcite light’,aluminium magnesium carbonate hydroxide hydrate. Altacite displays ayield stress of only 1 Pa and at this low yield stress would not besuitable for maintaining stable formulations wherein the activeingredient is of a hydrotalcite type comprising magnesium and iron or itis of insufficient yield stress to provide a stable formulation at adesirable particle size. and or dose level

Another product from Peckforton Pharmaceuticals Limited, HydrotalciteSuspension, also contains hydrotalcite. The formulation also containsVeegum regular which is a magnesium aluminum silicate used to alter therheology of liquid formulation. However, as this is an aluminium sourcethis product is not considered suitable for kidney patients.

Talcid is intended for the symptomatic relief in cases of heartburn,stomach hyperacidity. The active ingredient is ‘hydrotalcite light’,aluminium magnesium carbonate hydroxide hydrate, which suffers from thesame drawback of aluminium release and accumulation. Furthermore, theformulation contains bentonite which at higher concentrations can modifythe rheological characteristics of the formulation. Bentonite is acalcium hydrated aluminosilicate which may also release aluminium.Carboxymethylcellulose sodium is used as a thickening agent. Talciddisplays some yield stress but insufficient to provide a stableformulation at a desirable particle size.

The delivery of mixed metal compound is particularly problematic becausemixed metal compounds typically have a high particulate density (such asa density of around 1.9 g/ml). Due to the large difference in densitybetween such compounds and that of typical aqueous carrier fluids, mixedmetal compounds have a propensity to settle out on storage. The rheologyof the carrier fluid may be modified to increase the viscosity of thefluid and hence slow the settling rate of the suspended solids. Howeverbecause of the atypical high particulate density this has thedisadvantage that whilst the settling rate is reduced settling willstill occur over a relatively short time frame. Furthermore, the highfluid viscosity makes it difficult to re-disperse any settled mixedmetal compound.

U.S. Pat. No. 4,689,219 describes compositions comprising mixtures ofxanthan gum and locust bean gum in a specified range of ratios. Theformulation is packaged as a dry granule mix which is added to a drinkimmediately prior to consumption.

WO2007/135362 describes a formulation based on xanthan gum, PVP andglycerol containing a suspended non-steroidal anti-inflammatory drugwhere PVP acts a dispersant and glycerol as a density increasing agent.The optimal PVP concentration disclosed is 0.5 to about 3.5% w/v.Further, the suspended non-steroidal anti-inflammatory drug is presentat a concentration of up to 5% w/v. This compares to required deliverylevels of typically 10% w/v for mixed metal compounds.

IE153343 discloses an aqueous suspension concentrate composition ofpendimethalin, a pesticide. More specifically, IE153343 discloses theuse of a suspending agent, such as xanthan gum, at a concentrationbetween 0.02 and 3.0% w/v, in combination with thickening agents such aspolyvinyl-pyrrolidone (PVP). The proposed compositions also includesurfactants, dispensing agents or wetting agents and an antifoamingagent to provide a stable suspension.

U.S. Pat. No. 5,300,302 discloses a pharmaceutical delivery systemcomprising a composition comprising an drug homogeneously distributed ina water-dispersible gel excipient containing either xanthan gum or amixture of xanthan gum and methyl cellulose.

WO 03/013473 A1 teaches a colloidal silicon dioxide which may becombined with xanthan gum and a wetting agent in order to produce asuspension of drug particles that is substantially stable. It is statedthat silicon dioxide has a synergistic effect with xanthan gum andproduces a more stable suspension than otherwise possible U.S. Pat. No.5,112,604 discloses an aqueous formulation containing a drug substance;colloidal silicon dioxide; a hydrocolloid gum; a wetting agent; anantifoaming agent and a carbohydrate, which is stable for 90 days.

U.S. Pat. No. 7,300,670 discloses an aqueous pharmaceutical suspensionfor oral administration comprising at least one particulate drug with adensity of from about 0.9 to about 1.6 g/ml and an average particle sizeless than about 20 micron; at least one suspending polymer exhibitingplastic flow with or without additional viscosity-building agents thatprovides a yield value to the final suspension of about 0.2 to about 15Pa and an apparent viscosity at 100 sec⁻¹ of at least about 50 cps; aliquid phase with an absolute density difference from each particulatedrug of less than about 0.2 g/ml.

To provide sterile compositions, the prior art has taught that liquidcompositions may be irradiated. For example, U.S. Pat. No. 5,273,767discloses a modified, rapidly hydrating xanthan gum, prepared byirradiating non-irradiated xanthan gum with ionizing radiation, andfurthermore a process for sterilizing a food product comprisingnon-irradiated xanthan gum as a gelling hydrocolloid.

Although irradiation may provide sterility, it presents a number ofproblems when applied to liquids containing insoluble products. Forexample, “Formulation of a Sterile Surgical Lubricant”, Adams, I., S. S.Davis and R, Kenshaw. 1972, J. Pharm. Pharmacol., 24:178P describes thecomplete loss of gel structure in methyl celluloses followingirradiation. Applied Radiation Chemistry By Robert James Woods andAleksei Konstantinovich Pikaev teaches us that a standard irradiationdoses of 25 kGy is used in many countries, and 35 kGy in Scandinaviancountries, but that by control of the production environment microbialcontamination can be reduced to levels down to 10 kGy. (PublisherWiley-IEEE, 1994, ISBN 0471544523, 9780471544524). U.S. Pat. No.7,259,192 describes the depolymerization by high energy electron beamirradiation of xanthan gum at a preferred dose of 10 to 150 kGy.

SUMMARY OF THE INVENTION

In a first aspect the present invention provides a compositioncomprising

-   (i) a mixed metal compound containing at least one trivalent metal    selected from iron (III) and aluminium and at least one divalent    metal selected from of magnesium, iron, zinc, calcium, lanthanum and    cerium,-   (ii) xanthan gum-   (iii) at least one of    -   (a) polyvinyl pyrrolidone    -   (b) locust bean gum    -   (c) methyl cellulose        wherein the composition has been irradiated with ionising        radiation in an amount of at least 4 kGy.

In a second aspect the present invention provides a composition for useas a medicament, wherein the composition comprises

-   (i) a mixed metal compound containing at least one trivalent metal    selected from iron (III) and aluminium and at least one divalent    metal selected from of magnesium, iron, zinc, calcium, lanthanum and    cerium,-   (ii) xanthan gum-   (iii) at least one of    -   (a) polyvinyl pyrrolidone    -   (b) locust bean gum    -   (c) methyl cellulose        wherein the composition has been irradiated with ionising        radiation in an amount of at least 4 kGy.

In a third aspect the present invention provides a composition forbinding phosphate, wherein the composition comprises

-   (i) a mixed metal compound containing at least one trivalent metal    selected from iron (III) and aluminium and at least one divalent    metal selected from of magnesium, iron, zinc, calcium, lanthanum and    cerium,-   (ii) xanthan gum-   (iii) at least one of    -   (a) polyvinyl pyrrolidone    -   (b) locust bean gum    -   (c) methyl cellulose        wherein the composition has been irradiated with ionising        radiation in an amount of at least 4 kGy.

In a fourth aspect the present invention provides a composition for usein the treatment of hyperphosphataemia, wherein the compositioncomprises

-   (i) a mixed metal compound containing at least one trivalent metal    selected from iron (III) and aluminium and at least one divalent    metal selected from of magnesium, iron, zinc, calcium, lanthanum and    cerium,-   (ii) xanthan gum-   (iii) at least one of    -   (a) polyvinyl pyrrolidone    -   (b) locust bean gum    -   (c) methyl cellulose        wherein the composition has been irradiated with ionising        radiation in an amount of at least 4 kGy.

The present invention provides a carrier system for delivering insolublemixed metal compounds, namely those containing at least one trivalentmetal selected from iron (III) and aluminium and at least one divalentmetal selected from of magnesium, iron, zinc, calcium, lanthanum andcerium. The present system avoids the disadvantages of the prior artsystems either with regard to the problems associated with ingestion ofthe carrier or the detrimental effect that the carrier may have on theinsoluble compound. Critically, many prior art carriers aresignificantly detrimental to the phosphate binding capacity of mixedmetal compounds. Phosphate binding capacity is a key property of suchcompounds.

Many of the prior art excipients used to modify the rheology of thecarrier fluid are anionic in nature and may therefore interact with themixed metal compound, which binds phosphate by anion exchange.Consequently, the subsequent anion binding capacity of the mixed metalcompound (in this case for phosphate) is hindered.

The present invention provides a system in which the use of oil-basedcarriers is avoided. Such carriers can have the drawback of a highrelative calorific value. Such high calorific values are generallyconsidered to be undesirable and are particularly unsuitable forsubjects on a calorie restricted diet and/or who may consume thecomposition for a prolonged period of time.

The present invention is further advantageous in that it allows for highloads of mixed metal compound to be delivered. This is advantageous inthat the volume of product required to deliver a determined amount ofmixed metal compound is kept within acceptable amounts. The use of suchhigh loads is particularly advantageous for subjects who desire or arerequired to control fluid intake. Such a group is patients on dialysiswho must typically restrict the volume of liquid which they consume. Anyaqueous liquid dose formulation will contribute to the volume of liquidwhich the patient consumes, hence the volume of liquid must be kept to aminimum. As the mixed metal compound may be used for binding phosphatein a subject or for treating hyperphosphataemia, the composition is tobe administered to compounds suffering from renal disease who may inturn be undergoing dialysis. Thus the need to deliver high loads isparticularly applicable when delivering mixed metal compounds.

The present invention is further advantageous in that it provides for apreserved liquid composition wherein the addition of preservativecomponents is not required. Contrary to the teaching of the prior art,we have shown that by selection of a specific combination of suspensionmaterials and selection of a specific radiation dosage, a stable andpreserved composition may be provided. Prior art teachings in the fieldof effluent handling (Chromate immobilisation) showed that irradiationat 1000-6000 kGy is detrimental to mixed metal compounds and enhancesthe formation of spinell. In particular, we have shown that preservativecomponents are not required. Mixed metal compounds in an unbufferedaqueous system at the concentration range of interest (ca. 10% w/v)provide a relatively high pH (ca. 9.2 to 9.4). The high pH excludes theuse of all known, commercially available preservatives at concentrationseffective for microbial control and at levels that are safe for use in acomposition in a human population. For chemical preservation, the pH ofthe formulation must be limited to about 8.2 or below in order to permitthe use of preservatives at concentrations that are safe in the humanpopulation. The preservative may have some efficacy above pH 8.2 howeverthere is little margin for pH increase of the formulation, for example,on storage. A significant reduction in pH i.e. below approximately pH8.0 cannot be made without releasing magnesium from the mixed metalcompound structure. This has the effect of changing the mixed metalcompound structure and may also impair properties such as phosphatebinding performance of the mixed metal compound.

Hyperphosphataemia

As discussed herein in one aspect the present invention provides acomposition for use in the treatment of hyperphosphataemia, wherein thecomposition comprises

-   (i) a mixed metal compound containing at least one trivalent metal    selected from iron (III) and aluminium and at least one divalent    metal selected from of magnesium, iron, zinc, calcium, lanthanum and    cerium,-   (ii) xanthan gum-   (iii) at least one of    -   (a) polyvinyl pyrrolidone    -   (b) locust bean gum    -   (c) methyl cellulose        wherein the composition has been irradiated with ionising        radiation in an amount of at least 4 kGy.

Hyperphosphataemia is an electrolyte disturbance in which there is anabnormally elevated level of phosphate in blood. Hyperphosphataemia isfrequently seen in dialysis patients, as standard dialysis regimes areunable to remove the ingested phosphate load even with a low phosphatediet, and is associated with an increased risk of death and thedevelopment of vascular calcification. The presence ofhyperphosphataemia leads to hypocalcemia, secondary hyperparathyroidism,reduced 1.25 Vit D3 and progressive metabolic bone disease. Elevatedlevel of phosphate in blood is ultimately responsible for the increasein vascular calcification, but recent studies have also suggested thatthe process may additionally be influenced by 1.25 Vit D3 and anelevated calcium-phosphate product. Patients who have chronicallyuncontrolled hyperphosphataemia develop progressively extensive softtissue calcifications due to the deposit of Calcium/phosphate productinto skin, joints, tendons, ligaments. Eye deposits of calcium/phosphateproduct have also been described.

Control of serum phosphate levels using oral phosphate binders has,therefore, become a key therapeutic target in the management of dialysispatients. These binders, taken with food, render the contained phosphateinsoluble and, therefore, non-absorbable.

For ease of reference, these and further aspects of the presentinvention are now discussed under appropriate section headings. However,the teachings under each section are not necessarily limited to eachparticular section.

Preferred Aspects

Component (i)—Mixed Metal Compound

The mixed metal compound utilised in the present invention may be anymixed metal compound containing at least one trivalent metal selectedfrom iron (III) and aluminium and at least one divalent metal selectedfrom of magnesium, iron, zinc, calcium, lanthanum and cerium. In onepreferred aspect, the mixed metal compound contains at least iron (III)and at least magnesium.

Preferably, the compound is of formula I

M^(II) _(1-x)M^(III) _(x)(OH)₂A^(n−) _(y) .mH₂O  (I)

wherein M^(II) is one or more bivalent metals and is at least Mg²⁺;M^(III) is one or more trivalent metals and is at least Fe³⁺;A^(n−) is one or more n-valent anions and is at least CO₃ ²⁻;(Σyn)/x is from 0.5 to 1.50<x≦0.4,0<y≦1 and0<m≦10.(Σyn)/x may preferably be from 0.6 to 1.4, such as 0.7 to 1.3, such as0.8 to 1.2, such as 0.9 to 1.1, such as approximately 1, such as 1.0.

In one preferred aspect the compound has an aluminium content of lessthan 10,000 ppm, more preferably less than 7,000 ppm, more preferablyless than 5,000 ppm, more preferably less than 3,000 ppm, morepreferably less than 1000 ppm, more preferably less than 700 ppm, morepreferably less than 500 ppm, more preferably less than 300 ppm, morepreferably less than 200 ppm, most preferred 100 ppm, more preferablyless than 50 ppm, most preferably 30 ppm.

In one aspect the mixed metal compound is a compound as described inWO99/015189.

In one aspect the mixed metal compound is a compound as described inWO2006/085079

In one aspect the mixed metal compound is a compound as described in WO2009/050468.

In one aspect the mixed metal compound is a compound prepared inaccordance with British Patent Application No. 0913525.2.

Preferably the compound has a d50 average particle size of less than 300μm.

Preferably the compound has a d50 average particle size of less than 200μm.

Preferably the compound has a d50 average particle size of less than 100μm.

Preferably the compound has a d50 average particle size of from 2 to 50μm. Preferably the compound has a d50 average particle size of from 2 to30 μm.

The present invention encompasses products obtained by virtue of furthertreatment. In one aspect the dried crude product is milled. Morepreferably the dried crude product is milled to a d50 average particlesize of less than 10 μm, yet more preferably the dried crude product ismilled to a d50 average particle size from 2-10 μm. most preferred thedried crude product is milled to a d50 average particle size from 2-7μm, yet most preferred the dried crude product is milled to a d50average particle size of approximately 5 μm.

The physical stability of the present composition may be furtherimproved by reducing the particle size of the mixed metal compound bye.g. micronisation or wet milling.

The physical stability of the present composition may also be furtherimproved by drying the mixed metal compound prior to incorporation inthe composition. We found, surprisingly, that drying the mixed metalcompound to a moisture content of <15% w/w produces a mixed metalcompound which is stable in the present aqueous liquid formulation. Bycontrast, un-dried mixed metal compound (i.e. mixed metal compoundsynthesised by reaction in the normal way but washed and filteredwithout drying) is less stable when made up into a liquid.

In one preferred aspect the mixed metal compound is present in an amountof 8 to 12 w/v, more preferably the mixed metal compound is present inan amount of approximately 10 w/v.

The mixed metal compound may have a particle density (as measured inaccordance with method 20) of greater than 1.6 g/ml, or greater than 1.9g/ml. Moreover, the difference between the particle density of the mixedmetal compound and the fluid of the composition (typically comprised ofcomponent (ii) and component (iii)) is greater than 0.2 g/ml.

Irradiation

As discussed herein the present composition is irradiated with ionisingradiation in an amount of at least 4 kGy. Preferably the composition hasbeen irradiated with ionising radiation in an amount of at least 6 kGy,such as in an amount of at least 8 kGy, such as in an amount of at least10 kGy. Preferably the composition has been irradiated with ionisingradiation in an amount of no greater than 20 kGy, such as in an amountof no greater than 15 kGy, such as in an amount of no greater than 12kGy, such as in an amount of no greater than 10 kGy. The presentcomposition may be irradiated with ionising radiation in an amount of 1to 15 kGy, such as 2 to 14 kGy, such as 4 to 12 kGy, such as 6 to 10kGy. Preferably the composition has been irradiated with ionisingradiation in an amount of from 4 to 20 kGy, such as in an amount of from4 to 15 kGy, such as in an amount of from 4 to 12 kGy, such as in anamount of from 4 to 10 kGy. Preferably the composition has beenirradiated with ionising radiation in an amount of from 6 to 20 kGy,such as in an amount of from 6 to 15 kGy, such as in an amount of from 6to 12 kGy, such as in an amount of from 6 to 10 kGy.

Any suitable source of ionising irradiation may be used to provide thedesired level of irradiation. It is envisaged that electron beam, gammaand x-ray irradiation will be preferred.

Component (ii)—Xanthan Gum

Xanthan gum is a natural anionic biopolysaccharide made up of differentmonosacharides, mannose, glucose and glucuronic acids. It has theadvantage over other common natural polymers of resisting degradation byenzymes. Suspensions using xanthan gums have the advantage that once theyield stress is exceeded, they are shearing thinning i.e. the viscosityreduces with increasing shear input. Therefore, if settling occurs,shear input can be applied (by, for example shaking of the liquidcontainer) to reduce the viscosity and thus aid re-dispersion of anysettled solids. As discussed herein, the present composition mustcontain xanthan gum. One skilled in the art will appreciate that thexanthan gum may be present in any suitable amount sufficient to achievethe aims of the invention.

In one aspect the xanthan gum is present in an amount of no greater than10 wt %, preferably in an amount of no greater than 7 wt %, preferablyin an amount of no greater than 5 wt %, preferably in an amount of nogreater than 3 wt %, preferably in an amount of no greater than 2 wt %,preferably in an amount of no greater than 1.5 wt %, preferably in anamount of no greater than 1 wt %, preferably in an amount of no greaterthan 0.8 wt %, preferably in an amount of no greater than 0.6 wt %,preferably in an amount of no greater than 0.5 wt % based on weight ofthe composition.

In one aspect the xanthan gum is present in an amount of no less than0.01 wt %, preferably in an amount of no less than 0.02 wt %, preferablyin an amount of no less than 0.03 wt %, preferably in an amount of noless than 0.05 wt %, preferably in an amount of no less than 0.08 wt %,preferably in an amount of no less than 0.1 wt %, preferably in anamount of no less than 0.2 wt %, preferably in an amount of no less than0.3 wt % based on weight of the composition.

In one aspect the xanthan gum is present in an amount of from 0.01 to 10wt %, preferably in an amount of from 0.02 to 7 wt %, preferably in anamount of from 0.03 to 5 wt %, preferably in an amount of from 0.05 to 3wt %, preferably in an amount of from 0.08 to 2 wt %, preferably in anamount of from 0.1 to 1 wt %, preferably in an amount of from 0.2 to 0.8wt %, preferably in an amount of from 0.2 to 0.6 wt %, preferably in anamount of from 0.2 to 0.5 wt %, preferably in an amount of from 0.3 to0.5 wt % based on weight of the composition.

Component (iii)

As discussed herein, the present composition must contain at least oneof (a) polyvinyl pyrrolidone, (b) locust bean gum, and (c) methylcellulose. It will be appreciated by one skilled in the art that by atleast of it is meant that one of the listed components may be present,two of the listed components may be present or all three of the listedcomponents may be present. The one, two or three listed components maybe present in any suitable amount sufficient to achieve the aims of theinvention.

In one aspect the present composition contains polyvinyl pyrrolidone. Inone aspect the present composition contains locust bean gum. In oneaspect the present composition contains methyl cellulose. In one aspectthe present composition contains polyvinyl pyrrolidone and locust beangum. In one aspect the present composition contains polyvinylpyrrolidone and methyl cellulose. In one aspect the present compositioncontains locust bean gum and methyl cellulose. In one aspect the presentcomposition contains polyvinyl pyrrolidone, locust bean gum, and methylcellulose.

Locust bean gum is a high molecular weight, hydrophilic polysaccharide.It is non-ionic and is therefore unlikely to compete with phosphate bybinding to the mixed metal compound.

In one aspect component (iii) is present in an amount of no greater than10 wt %, preferably in an amount of no greater than 7 wt %, preferablyin an amount of no greater than 5 wt %, preferably in an amount of nogreater than 3 wt %, preferably in an amount of no greater than 2 wt %,preferably in an amount of no greater than 1.5 wt %, preferably in anamount of no greater than 1 wt %, preferably in an amount of no greaterthan 0.8 wt %, preferably in an amount of no greater than 0.6 wt %,preferably in an amount of no greater than 0.5 wt % based on weight ofthe composition. It will be understood that each of the above amountsrefers to the combined total amount of (a) polyvinyl pyrrolidone, (b)locust bean gum, and (c) methyl cellulose.

In one polyvinyl pyrrolidone is present in an amount of no greater than10 wt %, preferably in an amount of no greater than 7 wt %, preferablyin an amount of no greater than 5 wt %, preferably in an amount of nogreater than 3 wt %, preferably in an amount of no greater than 2 wt %,preferably in an amount of no greater than 1.5 wt %, preferably in anamount of no greater than 1 wt %, preferably in an amount of no greaterthan 0.8 wt %, preferably in an amount of no greater than 0.6 wt %,preferably in an amount of no greater than 0.5 wt % based on weight ofthe composition.

In one aspect locust bean gum is present in an amount of no greater than10 wt %, preferably in an amount of no greater than 7 wt %, preferablyin an amount of no greater than 5 wt %, preferably in an amount of nogreater than 3 wt %, preferably in an amount of no greater than 2 wt %,preferably in an amount of no greater than 1.5 wt %, preferably in anamount of no greater than 1 wt %, preferably in an amount of no greaterthan 0.8 wt %, preferably in an amount of no greater than 0.6 wt %,preferably in an amount of no greater than 0.5 wt % based on weight ofthe composition.

In one aspect methyl cellulose is present in an amount of no greaterthan 10 wt %, preferably in an amount of no greater than 7 wt %,preferably in an amount of no greater than 5 wt %, preferably in anamount of no greater than 3 wt %, preferably in an amount of no greaterthan 2 wt %, preferably in an amount of no greater than 1.5 wt %,preferably in an amount of no greater than 1 wt %, preferably in anamount of no greater than 0.8 wt %, preferably in an amount of nogreater than 0.6 wt %, preferably in an amount of no greater than 0.5 wt% based on weight of the composition.

In one aspect component (iii) is present in an amount of no less than0.01 wt %, preferably in an amount of no less than 0.02 wt %, preferablyin an amount of no less than 0.03 wt %, preferably in an amount of noless than 0.05 wt %, preferably in an amount of no less than 0.08 wt %,preferably in an amount of no less than 0.1 wt %, preferably in anamount of no less than 0.2 wt %, preferably in an amount of no less than0.3 wt % based on weight of the composition. It will be understood thateach of the above amounts refers to the combined total amount of (a)polyvinyl pyrrolidone, (b) locust bean gum, and (c) methyl cellulose.

In one aspect polyvinyl pyrrolidone is present in an amount of no lessthan 0.01 wt %, preferably in an amount of no less than 0.02 wt %,preferably in an amount of no less than 0.03 wt %, preferably in anamount of no less than 0.05 wt %, preferably in an amount of no lessthan 0.08 wt %, preferably in an amount of no less than 0.1 wt %,preferably in an amount of no less than 0.2 wt %, preferably in anamount of no less than 0.3 wt % based on weight of the composition.

In one locust bean gum is present in an amount of no less than 0.01 wt%, preferably in an amount of no less than 0.02 wt %, preferably in anamount of no less than 0.03 wt %, preferably in an amount of no lessthan 0.05 wt %, preferably in an amount of no less than 0.08 wt %,preferably in an amount of no less than 0.1 wt %, preferably in anamount of no less than 0.2 wt %, preferably in an amount of no less than0.3 wt % based on weight of the composition.

In one aspect methyl cellulose is present in an amount of no less than0.01 wt %, preferably in an amount of no less than 0.02 wt %, preferablyin an amount of no less than 0.03 wt %, preferably in an amount of noless than 0.05 wt %, preferably in an amount of no less than 0.08 wt %,preferably in an amount of no less than 0.1 wt %, preferably in anamount of no less than 0.2 wt %, preferably in an amount of no less than0.3 wt % based on weight of the composition.

In one aspect component (iii) is present in an amount of from 0.01 to 10wt %, preferably in an amount of from 0.02 to 7 wt %, preferably in anamount of from 0.03 to 5 wt %, preferably in an amount of from 0.05 to 3wt %, preferably in an amount of from 0.08 to 2 wt %, preferably in anamount of from 0.1 to 1 wt %, preferably in an amount of from 0.2 to 0.8wt %, preferably in an amount of from 0.2 to 0.6 wt %, preferably in anamount of from 0.2 to 0.5 wt %, preferably in an amount of from 0.3 to0.5 wt % based on weight of the composition. It will be understood thateach of the above amounts refers to the combined total amount of (a)polyvinyl pyrrolidone, (b) locust bean gum, and (c) methyl cellulose.

In one aspect polyvinyl pyrrolidone is present in an amount of from 0.01to 10 wt %, preferably in an amount of from 0.02 to 7 wt %, preferablyin an amount of from 0.03 to 5 wt %, preferably in an amount of from0.05 to 3 wt %, preferably in an amount of from 0.08 to 2 wt %,preferably in an amount of from 0.1 to 1 wt %, preferably in an amountof from 0.2 to 0.8 wt %, preferably in an amount of from 0.2 to 0.6 wt%, preferably in an amount of from 0.2 to 0.5 wt %, preferably in anamount of from 0.3 to 0.5 wt % based on weight of the composition.

In one aspect locust bean gum is present in an amount of from 0.01 to 10wt %, preferably in an amount of from 0.02 to 7 wt %, preferably in anamount of from 0.03 to 5 wt %, preferably in an amount of from 0.05 to 3wt %, preferably in an amount of from 0.08 to 2 wt %, preferably in anamount of from 0.1 to 1 wt %, preferably in an amount of from 0.2 to 0.8wt %, preferably in an amount of from 0.2 to 0.6 wt %, preferably in anamount of from 0.2 to 0.5 wt %, preferably in an amount of from 0.3 to0.5 wt % based on weight of the composition.

In one aspect methyl cellulose is present in an amount of from 0.01 to10 wt %, preferably in an amount of from 0.02 to 7 wt %, preferably inan amount of from 0.03 to 5 wt %, preferably in an amount of from 0.05to 3 wt %, preferably in an amount of from 0.08 to 2 wt %, preferably inan amount of from 0.1 to 1 wt %, preferably in an amount of from 0.2 to0.8 wt %, preferably in an amount of from 0.2 to 0.6 wt %, preferably inan amount of from 0.2 to 0.5 wt %, preferably in an amount of from 0.3to 0.5 wt % based on weight of the composition.

Component (iv) Sweeteners

Optionally, the palatability of the formulation may be improved by theaddition of sweeteners (either alone or in combination with sorbitol)and/or flavourings. For example, sweeteners such as AcesulfameK/Aspartame, Xylitol, Thaumatin (Talin) and Saccharin; and flavouringssuch as Butterscotch, Caramel, Vanilla, Mild peppermint and Strawberry,may be used.

Composition

The preferred absolute amounts of xanthan gum and component (iii),namely at least one of (a) polyvinyl pyrrolidone (b) locust bean gum and(c) methyl cellulose are defined herein. The ratio of xanthan gum andcomponent (iii) may be any suitable ratio within the absolute amountsdescribed herein. In one aspect the xanthan gum and component (iii) arepresent in a ratio of 2:1 to 1:2. Preferably the xanthan gum andcomponent (iii) are present in a ratio of approximately 1:1.

When the composition comprises at least polyvinyl pyrrolidone,preferably the composition comprises (ii) xanthan gum and (iii)polyvinyl pyrrolidone, wherein the xanthan gum and polyvinyl pyrrolidoneare present in a ratio of approximately 2:1. In this aspect preferablythe composition has been irradiated with ionising radiation in an amountof at least 8 kGy.

When the composition comprises at least locust bean gum, preferably thecomposition comprises (ii) xanthan gum and (iii) locust bean gum,wherein the xanthan gum and locust bean gum are present in a ratio ofapproximately 1:1. In this aspect preferably the composition has beenirradiated with ionising radiation in an amount of at least 6 kGy.

When the composition comprises at least methyl cellulose, preferably thecomposition comprises (ii) xanthan gum and (iii) methyl cellulose,wherein the xanthan gum and methyl cellulose are present in a ratio ofapproximately 1:1. In this aspect preferably the composition has beenirradiated with ionising radiation in an amount of at least 10 kGy.

The following compositions are preferred

Polyvinyl Pyrrolidone containing compositions xanthan gum polyvinylpyrrolidone based on weight of the composition from 0.01 to 10 wt % from0.01 to 10 wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from0.05 to 3 wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; orfrom 0.3 to 0.5 wt %. from 0.02 to 7 wt % from 0.01 to 10 wt %; or from0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %; or from0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from0.03 to 5 wt % from 0.01 to 10 wt %; or from 0.02 to 7 wt %; or from0.03 to 5 wt %; or from 0.05 to 3 wt %; or from 0.08 to 2 wt %; or from0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; or from0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from 0.05 to 3 wt % from 0.01to 10 wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05to 3 wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to0.8 wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3to 0.5 wt %. from 0.08 to 2 wt % from 0.01 to 10 wt %; or from 0.02 to 7wt %; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %; or from 0.08 to 2wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from 0.2 to 0.6wt %; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from 0.1 to 1 wt% from 0.01 to 10 wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %;or from 0.05 to 3 wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %;or from 0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt%; or from 0.3 to 0.5 wt %. from 0.2 to 0.8 wt % from 0.01 to 10 wt %;or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %;or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %;or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt%. from 0.2 to 0.6 wt % from 0.01 to 10 wt %; or from 0.02 to 7 wt %; orfrom 0.03 to 5 wt %; or from 0.05 to 3 wt %; or from 0.08 to 2 wt %; orfrom 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; orfrom 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from 0.2 to 0.5 wt % from0.01 to 10 wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from0.05 to 3 wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; orfrom 0.3 to 0.5 wt %. from 0.3 to 0.5 wt %. from 0.01 to 10 wt %; orfrom 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %; orfrom 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; orfrom 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %.

Locust Bean Gum containing compositions xanthan gum locust bean gumbased on weight of the composition from 0.01 to 10 wt % from 0.01 to 10wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05 to 3wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3 to0.5 wt %. from 0.02 to 7 wt % from 0.01 to 10 wt %; or from 0.02 to 7 wt%; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %; or from 0.08 to 2 wt%; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from 0.2 to 0.6 wt%; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from 0.03 to 5 wt %from 0.01 to 10 wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; orfrom 0.05 to 3 wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; orfrom 0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %;or from 0.3 to 0.5 wt %. from 0.05 to 3 wt % from 0.01 to 10 wt %; orfrom 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %; orfrom 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; orfrom 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %.from 0.08 to 2 wt % from 0.01 to 10 wt %; or from 0.02 to 7 wt %; orfrom 0.03 to 5 wt %; or from 0.05 to 3 wt %; or from 0.08 to 2 wt %; orfrom 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; orfrom 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from 0.1 to 1 wt % from0.01 to 10 wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from0.05 to 3 wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; orfrom 0.3 to 0.5 wt %. from 0.2 to 0.8 wt % from 0.01 to 10 wt %; or from0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %; or from0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from0.2 to 0.6 wt % from 0.01 to 10 wt %; or from 0.02 to 7 wt %; or from0.03 to 5 wt %; or from 0.05 to 3 wt %; or from 0.08 to 2 wt %; or from0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; or from0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from 0.2 to 0.5 wt % from 0.01to 10 wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05to 3 wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to0.8 wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3to 0.5 wt %. from 0.3 to 0.5 wt %. from 0.01 to 10 wt %; or from 0.02 to7 wt %; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %; or from 0.08 to2 wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from 0.2 to0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %.

Methyl Cellulose containing compositions xanthan gum methyl cellulosebased on weight of the composition from 0.01 to 10 wt % from 0.01 to 10wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05 to 3wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3 to0.5 wt %. from 0.02 to 7 wt % from 0.01 to 10 wt %; or from 0.02 to 7 wt%; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %; or from 0.08 to 2 wt%; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from 0.2 to 0.6 wt%; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from 0.03 to 5 wt %from 0.01 to 10 wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; orfroi 0.05 to 3 wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; orfrom 0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %;or from 0.3 to 0.5 wt %. from 0.05 to 3 wt % from 0.01 to 10 wt %; orfrom 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %; orfrom 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; orfrom 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %.from 0.08 to 2 wt % from 0.01 to 10 wt %; or from 0.02 to 7 wt %; orfrom 0.03 to 5 wt %; or from 0.05 to 3 wt %; or from 0.08 to 2 wt %; orfrom 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; orfrom 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from 0.1 to 1 wt % from0.01 to 10 wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from0.05 to 3 wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; orfrom 0.3 to 0.5 wt %. from 0.2 to 0.8 wt % from 0.01 to 10 wt %; or from0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %; or from0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from0.2 to 0.6 wt % from 0.01 to 10 wt %; or from 0.02 to 7 wt %; or from0.03 to 5 wt %; or from 0.05 to 3 wt %; or from 0.08 to 2 wt %; or from0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from 0.2 to 0.6 wt %; or from0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %. from 0.2 to 0.5 wt % from 0.01to 10 wt %; or from 0.02 to 7 wt %; or from 0.03 to 5 wt %; or from 0.05to 3 wt %; or from 0.08 to 2 wt %; or from 0.1 to 1 wt %; or from 0.2 to0.8 wt %; or from 0.2 to 0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3to 0.5 wt %. from 0.3 to 0.5 wt %. from 0.01 to 10 wt %; or from 0.02 to7 wt %; or from 0.03 to 5 wt %; or from 0.05 to 3 wt %; or from 0.08 to2 wt %; or from 0.1 to 1 wt %; or from 0.2 to 0.8 wt %; or from 0.2 to0.6 wt %; or from 0.2 to 0.5 wt %; or from 0.3 to 0.5 wt %.

A highly preferred composition comprises

-   (i) a mixed metal compound containing at least one trivalent metal    selected from iron (III) and aluminium and at least one divalent    metal selected from of magnesium, iron, zinc, calcium, lanthanum and    cerium,-   (ii) xanthan gum in an amount of from 0.3 to 0.5 wt % based on the    total composition-   (iii) locust bean gum in an amount of from 0.3 to 0.5 wt % based on    the total composition; wherein the composition has been irradiated    with ionising radiation in an amount of at least 4 kGy, such as from    4 to 10 kGy, such as at least 6 kGy, or such as from 6 to 10 kGy.

The present composition may contain one or more further components. Inone preferred aspect, the composition is a pharmaceutical compositionand further comprises (iv) one or more pharmaceutically acceptableadjuvants, excipients, diluents or carriers.

In one preferred aspect the composition is substantially free of awetting agent. Many insoluble drugs require wetting agents, e.g. todisperse the drug, or antifoaming agents, to prevent the inclusion ofair bubbles in the formulation. We have found the mixed metal compoundwhen incorporated in the present composition does not require a wettingagent. This effect and the exclusion of a wetting agent is particularlypronounced when the mixed metal compound has a magnesium iron ratiobetween 1.5 and 2.5 and contains carbonate anions. By “substantiallyfree of a wetting agent” it is meant the composition contains wettingagents in an amount of no greater than 10 wt %, preferably in an amountof no greater than 1 wt %, preferably in an amount of no greater than0.5 wt %, preferably in an amount of no greater than 0.3 wt %,preferably in an amount of no greater than 0.22 wt %, preferably in anamount of no greater than 0.1 wt %, preferably in an amount of nogreater than 0.05 wt %, preferably in an amount of no greater than 0.02wt %, preferably in an amount of no greater than 0.01 wt %, preferablyin an amount of no greater than 0.005 wt %, preferably in an amount ofno greater than 0.001 wt %, preferably in an amount of no greater than0.0001 wt %, preferably in an amount which is not measurable based onweight of the composition.

Another aspect to the invention is the combination of excipients has theeffect of preventing any sensation of ‘grittiness’, due to the mixedmetal compound component, in the mouth.

Optionally, the palatability of the formulation may be improved by theaddition of sweeteners (either alone or in combination with sorbitol)and/or flavourings. For example, sweeteners such as AcesulfameK/Aspartame, Xylitol, Thaumatin (Talin) and Saccharin; and flavouringssuch as Butterscotch, Caramel, Vanilla, Mild peppermint and Strawberry,may be used.

Packaging

We have found that sachets are a convenient form of container for singledose formulations with the further advantage that we have selectedpackaging material that can withstand irradiation. Preferably sachetsare selected which are suitable for single use only to avoid the needfor prolonged in use microbial stability formulations; this because theuse of preservatives are prohibitive in combinations with mixed metalcompounds. We have therefore developed formulations which have to meetall the requirements mentioned hereinbefore as well as providingcompatibility for use in sachets (i.e. pourability, homogeneity etc).Alternatively, the raw materials may be irradiated, however sources ofmicrobial and bacterial contamination must be eliminated from thesubsequent formulation make up and packaging stages to ensure sterility.This route is therefore less preferred.

The formulations are typically irradiated within 5 days afterpreparation of the formulation, preferably within 2 days, morepreferably within 1 day even more preferably immediately afterpreparation of the formulation. It will be appreciated to one skilled inthe art that initial microbial and fungal content of the raw materialsand the cleanliness of the formulation preparation (i.e. prior toirradiation) is such as to minimise microbial and fungal contamination.

Polymers for use in packaging, such as sachets, which show tolerance toirradiation include polystyrene, polyethylene, polyesters, polysulfone,polycarbonates, polyurethane, PVC, Silicone, Nylon, Polypropylene(irradiation grades) and Fluoroplastics.

Where metallic foils are used as materials of construction for sachets,care must be taken when selecting materials to avoid e.g. leaching intoor reaction with the sachet contents or should be coated with a suitablepolymer to avoid leaching.

Uses

As described herein, in one aspect the present invention provides thecomposition for use in the treatment of hyperphosphataemia. However, thecomposition is not limited to this particular use. The composition maybe used in accordance with the teachings of WO02009/016349 as anantacid.

Further Preferred Aspects and Advantages

A number of formulations each containing mixed metal compound have beenidentified, which deliver phosphate binding performance in a liquid doseform both initially and on storage, are of the appropriatemicrobiological quality, are physically stable and are of suitableappearance. The phosphate binding performance of the mixed metalcompound is not inhibited by the excipients and other additives used inthe formulations.

The first of these is formulation (see E24 below), based on an optimumcombination of xanthan gum (0.35% w/v) and locust bean gum (0.35% w/v)which is preserved by irradiation at an optimum dose level (6 kGy). Theformulation is preferred, having a good combination of physical andmicrobiological stability and phosphate binding efficacy/stability andsuitable for use in sachets. It is particularly suitable for single useformulations where prolonged in use stability is not required.

A second formulation (see E22 below) based on a combination of PVP (0.5%w/v) and xanthan gum (1.0% w/v) has been found which is preserved byirradiation at a dose level (8 kGy). The formulation is preferred,having good physical and microbiological stability and phosphate bindingefficacy/stability. It is particularly suitable for single useformulations where prolonged in use stability is not required.

A third formulation (see E10 below) based on a combination of methylcellulose with xanthan gum has been found which is preserved byirradiation at a dose level (10 kGy). This formulation has storagestability (physical, microbiological and phosphate bindingefficacy/stability). The formulation shows some reduction in phosphatebinding performance which occurs during accelerated storage stabilitytesting. It is particularly suitable for single use formulations whereprolonged in use stability is not required.

We have found that sachets are a convenient form of container for singledose formulations with the further advantage that the packaging materialcan be selected to withstand irradiation.

The present invention will now be described in further detail by way ofexample only with reference to the accompanying figures in which:—

FIG. 1 shows a graph; and

FIG. 2 shows a graph.

The present invention will now be described in further detail in thefollowing examples.

Rheology

Formulations with a yield stress have the theoretical ability to suspendsolids within the formulation indefinitely. There was therefore a needto determine a minimum yield stress.

The theoretical minimum yield value (Pa) (calculated according to Method2) to suspend the mixed metal compound was 0.2 Pa. Thickening agentswere selected at a concentration which would provide a yield stressabove the minimum critical value to prevent gravity-induced settling.The rheology of aqueous systems was then further assessed according toMethod 3.

Because the formulation must be able to be handled during manufactureand poured and/or squeezed from a container during use, the yield valuemust not be more than 19 Pa Of course, if the formulation is to besqueezed from a sachet, for example, higher yield stress values might beacceptable but are preferably limited to less than 30 Pa (to maintainpatient palatability and or texture).

The formulation must be easy to mix, pour or squeeze and swallow, whilstmaintaining the mixed metal compound in suspension and stable uponstorage. Consequently there is a need for a formulation that is of lowviscosity at high shear and of high viscosity at low shear.

Thus an optimum range of yield stress and a low viscosity at high shearand of high viscosity at low shear exists. An optimum yield stress from0.5 to approximately 19 Pa was identified experimentally, using agravimetric settling test to establish the minimum yield value, and avisual assessment of ‘pourability’ which was found to determine themaximum yield stress.

No Excipient (Control)

A mixture of the micronised mixed metal compound in water (5% w/v mixedmetal compound) was prepared, however the mixed metal compound settledout rapidly and the yield stress was less than 0.5 Pa. Thus thecriterion of a physically stable formulation was not met.

Single Materials Alginate (Comparative)

Mixtures of micronised mixed metal compound (5% w/v) with alginic acid(sodium, from brown algae, 3,500 cp for a 2% solution), (1 and 2% w/v,respectively) and water were prepared, the mixed metal compound settledrapidly even in the presence of relatively high concentrations ofalginate. The formulations had no measurable yield stress and thus thecriterion of a physically stable formulation was not met.

Carbopol 974 P NF (Comparative)

Carbomer 974 P NF is a polyacrylic acid which requires neutralisation ofthe acid functional group using a base to produce negatively chargedcarboxylate groups. This causes the polymer to uncoil and hence thickenaqueous systems.

A mixture of micronised mixed metal compound (5% w/v) with Carbopol 974P NF (0.2% w/v) and water was prepared. The phosphate bindingperformance of the formulation is acceptable, the combination of mixedmetal compound with Carbopol caused the system to ‘gel’ and it could nolonger be poured.

Microcrystalline Cellulose (Comparative)

A mixture of micronised mixed metal compound (5% w/v) withmicrocrystalline cellulose 2% w/v) and water was prepared, again themixed metal compound settled rapidly. Thus the criterion of a physicallystable formulation was not met.

Methyl Cellulose (Comparative)

Mixtures of micronised mixed metal compound (5% w/v) with methylcellulose (2 and 3% w/v, 400 cP grade; and 1%, 1500 cP grade,respectively) and water were prepared, again the mixed metal compoundsettled rapidly. Thus the criterion of a physically stable formulationwas not met.

Colloidal Silica (Comparative)

Colloidal silicas, such as Aerosil 200 (supplier: Evonik) are commonlyused to help structure liquid suspensions. Because of the small particlesize and other particle characteristics colloidal silica has the abilityto form a three-dimensional network in liquid systems. Colloidal silicacan be effectively used to modify the rheology of compositions. However,it was found that the combination of colloidal silica and mixed metalcompound, at a concentration of 0.5 and 10% w/v, respectively, failed toproduce a physically stable formulation (settles within 24 hours).

Xanthan Gum (Comparative)

Mixtures of mixed metal compound (5% w/v) with various concentrations ofxanthan gum (between 0.2 and 1% w/v, respectively) and water wereprepared. Whilst each of the formulations displayed an improvedstability (attributable in part to a measurable yield stress of between1 and 10 Pa), visible floccules of mixed metal compound were observed.This was deemed to be unacceptable. The formation of floccules is notgenerally consistent with a formulation having good physical stability.

Summary

In summary, of the single excipients tested none provided yield stresssuitable for suspension of the mixed metal compound

Combinations of More than One Material

In an attempt to solve the problem of visible floccules and optimisingthe preferred yield stress, various excipients were combined and testedat a range of concentrations. The composition of these formulations isgiven below in Tables 1, 2 and 3, below.

Xanthan Gum and Silica (Comparative)

Three different concentrations of colloidal silica were tested withthree different concentrations of xanthan gum producing a matrix of nineformulations. The rheology and physical stability of the formulationswere measured, and a qualitative assessment of the formulationappearance was made. Data are presented for the optimum formulation E1.

It was found that not all combinations of silica and xanthan gumproduced stable formulations. We found, surprisingly that only thosewhere silica is present in the approximate range of 0.1 to 0.5% w/v andxanthan gum 0.5 to 1.0% w/v and the sum of those agents is betweenapproximately 0.5 and 1.0% w/v were suitable (Formulation E1).

The inclusion of colloidal silica did not significantly modify thepreferential rheology of the formulation i.e. the advantageous yieldstress and shear thinning properties of the formulation were maintained.Contrary to the prior art there was no requirement for inclusion ofwetting or anti-foaming agents for proper dispersal of the mixed metalcompound.

Our data demonstrates that contrary to the art, most combinations ofxanthan gum and silica produce unstable suspensions of pharmaceuticalscontaining insoluble products. We discovered a suitable but narrow rangewhich was stable prior to irradiation (i.e. E1 formulation) however uponirradiation silica formulations were found to only provide sterileformulation when irradiated at very high levels (more than 10 kGy) thisin turn led to a decrease of the physical stability of the liquid(without being bound by theory it is believed that this is due tochanges in the excipients).

TABLE 1 Summary of Formulation E1 Composition, % w/v E1 Fermagate (mixedmetal 10 compound) Colloidal Silica 0.5 Xanthan Gum 0.5 Sorbitol 6 Sumthickening agents 1.0 Rheology Yield stress (Pa), Method 3 7 Physicalstability vol % sediment, Method 6 0 vol % sediment, Method 7 37.5

Microcrystalline Cellulose and Sodium Carboxymethylcellulose(Comparative) and Xanthan Gum and Locust Bean Gum

Avicel RC 591 is a water dispersible hydrocolloid used in thepreparation of pharmaceutical suspensions and emulsions. It is a spraydried blend of microcrystalline cellulose and sodiumcarboxymethylcellulose. Data in respect of this product is reported asFormulation E2 below.

Avicel CL 611 is also blend of microcrystalline cellulose and sodiumcarboxymethylcellulose, however it is more suitable for storage as a dryformulation whereby liquid is added only at the point of use.

TABLE 2 formulations based on Avicel. Composition, % w/v E2 E3 E4 E5Fermagate (mixed metal 10 10 10 10 compound) Avicel RC 591 1.5 1.5 1.3Avicel CL 611 0.3 1.3 Xanthan Gum 0.3 LBG 0.02 Sorbitol 6 Sum thickeningagents 1.5 1.5 1.6 1.62 Rheology Yield stress (Pa), Method 3 Yieldstress (Pa), Method 15 0.1 ND 5.5 4.5 ‘Pourability’, Method 4 Physicalstability Gravimetric test, Method 5 (1) ND ND ND vol % supernat't,Method 18 65 ND 0 0 Appearance Observation Little/no flocc ND = No Data(1). Forms small layer of supernatant liquor upon storage

Formulation E2 containing Avicel RC 591 was found to produce anacceptable formulation but had a higher degree of separation whencompared to E4 and E5. Formulation E3 was not physically stable andcould therefore not be assessed. This may have been a consequence oflimitations of the method of formulation make up.

Formulations E4 and E5 were developed with an optimised range ofexcipient combinations such as to provide physical stability,Surprisingly we found that the addition of a small quantity of LocustBean Gum (i.e. formulation E5) provided a formulation which was suitablefor storage as a liquid, contrary to its typical usage.

Xanthan Gum and Methyl Cellulose

Table 3 presents formulations E6 to E14 which are all based oncombinations of methyl cellulose and xanthan gum at differentconcentrations.

Three different concentrations of methyl cellulose were tested withthree different concentrations of xanthan gum producing a matrix of nineformulations. The rheology and physical stability of the formulationswere measured, and a qualitative assessment of the formulationappearance was made.

TABLE 3 Summary of Formulations, Formulations E6 to E14 E6 E7 E8 E9 E10E11 E12 E13 E14 Composition, % w/v Fermagate (mixed metal 10 10 10 10 1010 10 10 10 compound) Methyl cellulose 0.1 0.5 1 0.1 0.5 1 0.1 0.5 1Xanthan gum 0.1 0.1 0.1 0.5 0.5 0.5 1 1 1 Sorbitol 6 6 6 6 6 6 6 6 6 Sumthickening agents 0.2 0.6 1.1 0.6 1 1.5 1.1 1.5 2 Rheology Yield stress(Pa), Method 3 0.4 0.8 2.6 8 7 16.3 16.3 17 30 ‘Pourability’, Method 4very thick Physical stability Gravimetric test, Method 5 Note 1 Vol %sediment, Method 6 34.4 12.5 12.5 0 0 0 0 vol % sediment, Method 7 31.3<6.3 <6.3 <6.3 <6.3 Appearance Observation 1 Aearated Aearated some someminor floccu- floccu- floccu- lation lation lation Observation 2 bottombottom Aearated 12.5% 12.5% darker darker Note 1 Full separation in 24 h

From Table 3 and FIGS. 1 and 2 it can be seen that the optimum range ofmethyl cellulose is between 0.5 and 1.0% w/v. This produces a physicallystable formulation, with absence of aeration and absence of visibleflocculation.

From the data it is seen that excessive sedimentation (Method 5) occursat yield stress values up to 2.6 Pa. Even at higher yield stress values(8 Pa) sedimentation may still occur (Method 6) if the sum thickeningagent value is not maintained at above 0.6% w/v.

Pourability is acceptable at yield stress values of up to 17 Pa, but ispoor at values of 30 Pa.

Furthermore, excess amounts (above 1% w/v) of methyl cellulose werefound to hinder Pi binding.

The inclusion of methyl cellulose can prevent the appearance offlocculation but that flocculation may still occur in formulationscontaining 1% w/v xanthan gum.

It was found that some combinations of methyl cellulose and xanthan gumwere more preferred. Accelerated settling tests on formulations (allwith 6% w/v sorbitol, 10% w/v Fermagate mixed metal compound) containingxanthan gum at 0.1% w/v and methyl cellulose at 0.1, 0.5 and 1% w/vrespectively produced an excessive sediment volume (defined as beingmore than 10% v/v) in each case. Formulations combining xanthan gum at1% w/v with methyl cellulose at 0.1, 0.5 and 1% w/v all showed somedegree of flocculation and in some cases were difficult to pour(corresponding to a yield stress of around 19 Pa). Accelerated settlingtests on the formulation containing 0.5% w/v xanthan gum and 0.1% w/vmethyl cellulose produced an excessive sediment volume, whereas theformulation containing 0.5% w/v xanthan gum and 1% w/v methyl cellulosewas excessively aerated during preparation. Furthermore the latterformulation had the same sediment volume as the optimum 0.5% w/v xanthangum/0.5% w/v methyl cellulose formulation, with the disadvantage ofhigher overall suspending agent content.

The data (of Table 3) demonstrates the advantages of methyl celluloseover the use of silica as a thickening or “liquid structuring” agentpreventing flocculation. Contrary to the use of silica, we found thatmethyl cellulose was not affected by irradiation.

Contrary to the teachings of the prior art (Adams et al 1972) we did notobserve loss of gel structure in methyl cellulose following irradiationof liquids containing mixed metal compounds and Xanthan gum under thepreferred formulations discussed herein below.

Furthermore, phosphate (Pi) binding was initially not affected by thepresence of methylcellulose. Upon storage there was some inhibition ofPi binding in the presence of methyl cellulose but we found that thiscould be controlled by maintaining suitable lower levels of methylcellulose (such as from 0.5 to 1% w/v). The selection of lower levels ofmethyl cellulose also maintained the required yield stress (2.6-19 Pa)and did not increase the potential for flocculation or settling. Theviscosity of the formulation was such as to enable mixing, pouring orsqueezing from the sachet and allow swallowing with no grittiness inmouth. There is especially a need for a formulation that is of lowviscosity at high shear and of high viscosity at low shear and does nothave loss of gel structure following irradiation.

Consequently, the use of methylcellulose provides advantages, such asproviding a physically stable formulation, for liquids containing mixedmetal compounds and Xanthan gum.

In preferred aspects the following conditions are maintained:

-   -   sum thickening agents is maintained at above 0.6% w/v    -   methyl cellulose concentration is limited to less than 1% w/v        and more preferably from 0.5 to 1% w/v.    -   xanthan gum concentration limited to less than 1% w/v    -   Yield stress should be limited to between 2.6 Pa and 30 Pa.        Furthermore, if the sum thickening agents is below 0.6% w/v, the        minimum yield stress to prevent sedimentation is 8 Pa.

It was found that the inclusion of methyl cellulose in a formulationcontaining xanthan gum at certain preferred ratios of xanthan to methylcellulose also prevented the formation of visible floccules of mixedmetal compound.

Thus formulation E10 is preferred (high mixed metal compoundconcentration, yield stress in optimal range, shear thinning propertiesenabling re-dispersion of settled component, absence of visiblefloccules, physically stable under accelerated centrifugation test).Again, the advantageous rheology of the formulation was maintained andthere was no requirement for inclusion of wetting agents or anti-foamingagents for proper dispersal of the mixed metal compound.

Xanthan Gum and Polyvinyl Pyrrolidone (PVP)

Table 4 presents formulations E15 to E23 which are all based oncombinations of PVP (polyvinyl pyrrolidone) and xanthan gum at differentconcentrations.

TABLE 4 Summary of Formulations, Formulations E15 to E23 E15 E16 E17 E18E19 E20 E21 E22 E23 Composition, % w/v Fermagate (mixed metal 10 10 1010 10 10 10 10 10 compound) PVP 0.1 0.5 1 0.1 0.5 1 0.1 0.5 1 Xanthangum 0.1 0.1 0.1 0.5 0.5 0.5 1 1 1 sorbitol 6 6 6 6 6 6 6 6 6 Sumthickening agents 0.2 0.6 1.1 0.6 1 1.5 1.1 1.5 2 Rheology Yield stress(Pa), Method 3 0.4 0.4 0.45 6.4 6.25 9 16 15 18.8 ‘Pourability’, Method4 Physical stability Gravimetric test, Method 5 vol % sediment, Method 618.8 18.8 18.8 0.0 0.0 0.0 0.0 0.0 0.0 vol % sediment, Method 7 18.825.0 25.0 12.5 12.5 12.5 12.5 1.3 12.5 vol % supernat't, Method 6 vol %supernat't, Method 7 Appearance Observation Flocs Note (1). Forms smalllayer of supernatant liquor upon storage

Formulations E15 to E23 (Table 4)

It was found, surprisingly, that the combination of PVP when prepared incombination with Xanthan gum prevented the formation of visiblefloccules of mixed metal compound. For example, the physical stabilityupon storage (Accelerated settling test Method 6 and 7) was improved bymaintaining dose levels of Xanthan gum and PVP at dose levels of from0.5 to 1% w/v. Accelerated settling tests on the formulations (all with6% w/v sorbitol, 10% w/v mixed metal compound) containing xanthan gum at0.1% w/v and PVP at 0.1, 0.5 and 1% w/v, respectively and with xanthangum at 0.5% and PVP at 0.1, 0.5 and 1% w/v, respectively produced ansediment volume in all cases. Of the remaining formulations, theformulation combining xanthan gum at 1% w/v with PVP at 1% w/v was gellike, and formulation E21 showed some degree of settling. In summary,Table 3 demonstrates that the most stable formulations are obtainedwhere Xanthan gum and PVP are at a level from 0.5 to 1. Most stableformulation (E22) is obtained at levels of Xanthan gum and PVP atrespectively 1 and 0.5% w/v and the yield stress is from 10 to 20 Pa,more preferably 15 Pa. Thus formulation E22 is preferred as thisprovides a high mixed metal compound concentration of 10% w/v, yieldstress in a preferred range of from 10 to 20 Pa, shear thinningproperties enabling re-dispersion of settled component, absence ofvisible floccules, physically stable under accelerated centrifugationtest methods 6 and 7. Again, the advantageous rheology of theformulation was maintained and there was no requirement for inclusion ofwetting agents or anti-foaming agents for proper dispersal of the mixedmetal compound.

Xanthan Gum and Locust Bean Gum

Table 5 presents formulations E5 to E30 wherein PVP has been replaced byLocust Bean Gum (LBG) which are all based on combinations of Locust BeanGum and xanthan gum at different concentrations. Formulation E5additionally contains Avicel CL 611.

TABLE 5 Summary of Formulations E5 to E30 E5 E24 E25 E26 E27 E28 E29 E30Composition, % w/v Fermagate (mixed metal 10 10 10 10 10 10 10 10compound) Avicel CL 611 1.3 LBG 0.02 0.35 0.1 0.5 1 0.1 0.5 0.1 Xanthangum 0.3 0.35 0.1 0.1 0.1 0.5 0.5 1 sorbitol 6 6 6 6 6 6 6 Sum thickeningagents, % w/v 1.62 0.7 0.2 0.6 1.1 0.6 1 1.1 Rheology Yield stress (Pa),Method 3 0 5.5 2.5 ND ND ND ‘Pourability’, Method 4 Very runny ThickThicker Thick Thick Thick but than jelly jelly jelly flows 0.5/0.1 well(LBG/XG), flows well Yield Stress (Pa), Method 15 4.5 7 Physicalstability Gravimetric test, Method 5 Separates ND ND ND ND ND quicklyvol % sediment, Method 6 60.0 0 0 ND ND ND vol % sediment, Method 7 24.020 0 ND ND ND vol % supernat't, Method 6 0 0 0 ND ND ND vol %supernat't, Method 7 68 0 0 ND ND ND vol % supernat't, Method 18 0 0 NDND ND ND ND ND Appearance Observation 1 Little/ Little/ Floccu- Little/Little/ Little/ Little/ Little/ no flocc no flocc lates no flocc noflocc no flocc no flocc no flocc

From the data it is seen that excessive sedimentation (Method 7) occursat yield stress values below 2.5 Pa (method 3 data).

Pourability is acceptable at yield stress values of up to 5.5 (method3), but is poor at values of 19 Pa and above.

The inclusion of PVP can prevent the appearance of flocculation but thatflocculation may still occur where the sum thickening agentconcentration is up to 0.2% w/v.

Thus an optimum formulation exists:

-   -   sum thickening agents is maintained above 0.2% w/v.    -   yield stress limited to more than 5.5 Pa and up to 19 Pa

It was found, surprisingly, that the combination of Locust Bean Gum andxanthan gum as formulations E26 to E30 produced suspensions with novisible floccules of mixed metal compound. Formulation E25 wherein bothxanthan gum and Locust Bean Gum were 0.1% w/v did flocculate.Formulation E28, E29 and E30 had the appearance of a thick jelly whereasE26 and E27 also had the appearance of the thick jelly but had goodpourability. Thus the physical form of formulations E26 and E27 wasfound to be preferred where the xanthan gum was formulated at only 0.1%w/v. Results of the settling test were good for each. Based on theresults for E26 and E27 a formulation consisting of 0.35% w/v xanthangum and 0.35% w/v locust bean gum was ultimately selected to takeforward, this is denoted formulation E24. This shared the advantageousphysical form and absence of floccules of E26 and E27.

Irradiation Study

A number of preferred formulations were irradiated (parameters ofinvestigation included physical properties, phosphate binding andmicrobiological stability). Formulations are listed in Table 6, below.

TABLE 6 Physical Stability of mixed metal compound FormulationsFormulation E1 E10 E22 E3 E5 E24 Composition (% w/v) Fermagate (mixedmetal 10 10 10 10 10 10 compound) Colloidal Silica 0.5 Xanthan gum 0.50.5 1.0 0.3 0.35 Methyl Cellulose 0.5 Kollidon CL M (PVP) 0.5 Avicel RC591 1.5 Avicel CL 611 1.3 Locust Bean Gum 0.02 0.35 Sorbitol 70%solution 6 6 6 6 6 6 Water QS QS QS QS QS QS Absence of floccules YesYes Yes Yes Yes Yes Rheology Yield stress (Method 3, Pa) 7 7 9 ND ND NDYield stress (Method 15, Pa) 4.5 7 Physical stability Vol % sediment 0 00 ND ND ND (accelerated test, Method 6) Vol % sediment 37.5 <6.3 12.5 NDND ND (accelerated test, Method 7)

In summary we developed suitable formulations of combinations ofcomponent (i) the mixed metal compound, component (ii) xanthan gum (from0.1 to 1.0% w/v), component (iii) selected from one of (or combinations)of colloidal silica (Aerosil 200), methyl cellulose, blend ofmicrocrystalline cellulose and sodium carboxymethylcellulose (Avicel RC591 & CL 611 grades), PVP (Kollidon CL M) and Locust Bean Gum (from 0.1to 1% w/v) and component (iv) sweetening agent selected as sorbitol (6%,preferred range 3 to 12%).

The main function of component (i) the mixed metal compound is that itprovides phosphate binding capacity as well as functioning as a wettingagent.

The function of component (ii) the xanthan gum is its ability to producea large increase in the viscosity of the liquid and to impart a yieldstress upon the formulation. The viscosity of xanthan gum solutionsdecreases significantly with higher shear rates. This provides asuitable formulation for filling into sachets, in that the xanthan gumis thick enough at rest within the sachet to maintain homogeneity.However, the shear forces generated by e.g. filling, handling andsqueezing, thins the formulation, so that the formulation can be easilydosed into the sachet and readily be dispensed from it.

The function of component (iii) is to prevent flocculation and settling.To prevent flocculation and settling after irradiation we found thatpolyvinyl pyrrolidone, locust bean gum and methyl cellulose arepreferred.

Component (iv) was selected as a sugar substitute as low calorific valuesweeteners and is preferred for subjects who may consume the compositionfor a prolonged period of time.

The above combinations of excipients and mixed metal compound atpreferred concentration ranges have been found to meet the requirementof not significantly hindering phosphate binding, providing stableformulations upon storage (stable rheology, phosphate binding andsterility), preventing any sensation of ‘grittiness’ due to the mixedmetal compound component in the mouth and being compatible withsterilisation treatment by irradiation and providing appropriaterheology to enable use in sachets.

Preservation by Irradiation Sterilisation

A study was carried out to identify the optimum gamma irradiation doselevel for formulations described in Table 7.

The physical and chemical properties of each formulation were thentested at the following time points:—

-   1) Initial analysis after the manufacture of each batch.-   2) Post irradiation: All formulations were irradiated at an average    dose of 10 kGy.-   3) Storage Stability: All formulations were stressed at 60° C. for    one week after being irradiated. This was to help identify any    likely degradation which may be seen in the long term stability    study at less onerous conditions.

In order to meet the conflicting requirements of microbiologicalstability, physical stability and phosphate binding stability, anoptimum irradiation dose level should be defined.

Formulations were therefore irradiated at three radiation intensitylevels, 6, 8, and 10 kGy. The characterisation data for the 18 systemsis summarised below in Tables 8 and 9:

Excipients and mixed metal compound substance were taken from a singlebatch of material.

TABLE 7 Results for Irradiation Study - Physical Property FormulationE10 E4 E5 E24 0.5% w/v E22 E3 1.3% w/v 1.3% w/v 0.35% w/v Method Methyl0.5% w/v 0.5% w/v Avicel Avicel Locust Component (iii) — E1 cellulosePVP Avicel RC591 CL611 Bean Gum Rheology Yield Stress, Pa 15Irradiation, 0 kGy 6   7   17.5 0.1 5.5 4.5 7 6 kGy ND 0   10.5 0.2 3.54 7 8 kGy ND 0   8 0.2 1.4 3 6 10 kGy  4   0   7 0.15 1.75 1.25 5 PhaseAngle Delta, ° 16 Irradiation, 0 kGy 31.3  21.6  16.2 34.8 26.2 22.214.0 6 kGy ND 30.0  37.3 43.1 43.9 37.4 12.1 8 kGy ND 28.2  47.3 32.038.1 35.5 12.2 10 kGy  48.75  30.8  50.6 18.3 39.7 32.0 14.8 Storagestability, 6 kGy ND 34.4  45.2 24.3 30.9 26.4 10.6 8 kGy ND 56.0  56.723.7 34.9 22.1 14.8 10 kGy  80.64  56.5  65.1 38.9 56.1 26.4 22.4Complex Viscosity, Pa · s 17 Irradiation, 0 kGy 0.95 2.6 5.6 0.1 1.8 1.83.6 6 kGy ND 2.2 2.0 0.1 0.6 0.9 4.1 8 kGy ND 1.0 1.2 0.2 0.4 0.6 3.7 10kGy  0.49 1.0 1.0 0.3 0.5 0.6 2.5 Storage stability, 6 kGy ND 2.2 1.50.3 1.0 2.0 5.0 8 kGy ND 0.2 0.9 0.3 0.7 1.1 2.0 10 kGy  0.09 0.2 0.50.3 0.3 3.3 1.0 Physical Stability (vol % 18 supernatant) Irradiation, 0kGy 2   0*  0.5 65 0 0 0 6 kGy ND 0*  0 65 10 4.9 0 8 kGy ND 0*  0 65.941.5 12.2 0 10 kGy  2   10.8  4.9 67.5 40 15 0 Storage stability, 6 kGyND 5   0 65 37.5 27.5 0 8 kGy ND 7.5 5 66.7 47.6 42.5 0 10 kGy  16   4.9 4.9 70.7 57.5 50 0 Diffraction line half width, °2 14 theta  1.020.76 Irradiation 0 kGy 0.93  0.83 0.81 10 kGy  0.83  0.81 0.8 Storagestability 10 kGy  0.80 pH 11 Irradiation 0 kGy 8.6  10 kGy  8.2  9.2 9.2Storage stability 10 kGy  8.2  9   9.1 0 kGy sample, after 7 weeks 7.9 9   9.1 storage ND ND Results for Irradiation Study - Micro and EfficacyResults Formulation Method E1 E10 E22 E3 E4 E5 E24 Microbiology, cfu/mlIrradiation, 0 kGy 12 680 000      ND ND ND ND ND ND 6 kGy ND 0 20 0 05175 0 8 kGy ND 80 0 0 0 680 0 10 kGy  >680 000       0 0 0 0 0 0P-binding, mmol/gAPI Irradiation, 0 kGy 13 0.56 0.64 0.66 0.75 0.65 0.640.66 6 kGy ND 0.67 0.67 0.66 0.65 0.64 0.66 8 kGy ND 0.65 0.67 0.67 0.640.64 0.66 10 kGy  0.61 0.64 0.66 0.75 0.65 0.64 0.66 P-binding (storagestability), mmol/g API Storage stability testing at 13 40° C./75% RH, 1mnth ND ND ND ND ND ND ND Storage stability 6 kGy ND 0.61 0.64 0.6 0.60.6 0.6 8 kGy ND 10 kGy  0.56 0.52 0.63 0.61 0.58 0.59 0.62 0.48 0.560.66 0.59 0.58 0.61 ND No data

CONCLUSION Physical Stability

An absence of flocculation is best achieved by use of two excipients incombination, as previously described.

In the centrifugal separation test (indicator to determine the potentialfor settling) of formulation E1, less than 2% of separation occurred insamples tested immediately after manufacture and post irradiation; andincreased to 16% after storage stability testing.

For formulation E10 less than 2% of separation occurred in samplestested immediately after manufacture and post irradiation; and increasedto only 9% after storage stability testing.

For formulation E3 at all stages. The percentage for the solid layerfluctuates due to the formulation not being homogenous to start with. Inthe gravimetric separation test, after 30 minutes a clear layer ofseparation was observed for initial, post irradiation and after storagestability testing samples.

The preferred value for supernatant (% basis) is zero, this indicates noseparation under the accelerated separation test. Samples E22 and E24perform best according to this test.

Particle Size

We have found that an optimum particle size exists from 1 to 30 micronfor the mixed metal compound. If the particle size is too large, theyield stress required to suspend the particle will be too high andsubsequently the handling characteristics of the formulation will not beoptimal. For example, it may become too difficult to pour theformulation from a bottle, or squeeze it from a sachet. Additionally ata particle size of above about 200 micron, P-binding is reduced.Furthermore, above a particle size of approximately 30 micron, a‘gritty’ mouth feel may be found. The optimum particle size of theexcipients (i.e. components ii and iii) were selected such as to be verysimilar (i.e. less than 30 micron) to that of the mixed metal compoundto maintain homogeneity of the slurry.

Viscosity

The Viscous or loss modulus is a measure of the liquid like behaviour ofthe formulation. The phase angle, δ, is calculated from the Elastic andViscous modulus and is a measure of the gel strength, where

Tan δ=G″/G′

If δ<45° then the material is a gel and the lower the phase angle thestronger the gel. The Elastic modulus is a measure of the solid likebehaviour of the formulation.

The Elastic modulus and the Viscous modulus were highest for initial E1samples tested post manufacture; however they decreased followingirradiation, and then decreased further following storage stabilitytesting. The phase angle increased from an initial value of 31.3° to48.75° post irradiation and 80.64° after storage stability testing. Thissuggests the formulation became more liquid in behaviour primarilyfollowing storage and irradiation did not contribute significantly. Theyield stress decreased from approximately 6 to approximately 4 Pafollowing irradiation but this surprisingly did not lead to an increasein flocculation (settling).

The Elastic modulus and the Viscous modulus were highest for initial E10samples tested post manufacture; however they decreased followingirradiation, and then decreased further following storage stabilitytesting. The phase angle increased from an initial value of 16.570 to44.30° post irradiation and 49.24° after storage stability testing. Thissuggests the formulation became more liquid in behaviour primarilyfollowing irradiation and storage did not contribute significantly;however, these properties were found to maintain their suitability foruse in sachets. The yield stress decreased from approximately 12.5 toapproximately 6 Pa following irradiation but this surprisingly did notlead to an increase in flocculation.

No rheology was performed on formulation E3 because it formed anunstable suspension. Because the formulation is fast settling, sampleheterogeneity is an issue, giving highly variable results.

Irradiation

From the separation data (Table 7) it is seen that the response toirradiation and storage differs between formulations. Formulations E10,E22 and E24 all show physical stability, as demonstrated by the valuesof supernatant test, value of yield stress and absence of flocculationwhereas comparative formulations E3 and E4 do not.

E2 and E4 comprise Avicel and the data shows that these formulation arenot stable. E10 comprises methyl cellulose and xanthan gum whereas E2and E4 consisting of Avicel (which in turn is a mixture methyl celluloseand carboxymethyl) are not stable during irradiation.

The corresponding preferred yield stress range as defined in Method 3 isabout 7 to 17.5 Pa for pre-irradiation samples and about 5 to 10.5 Pafor post irradiation samples (depending upon the exact irradiation doseapplied). For pre-irradiated samples the preferred range for phaseangle, Delta, is about 14 to 16°. Again for pre-irradiated samples thepreferred complex viscosity range is about 3 to 6 Pa s.

Phosphate Binding

From Table 7 it can be seen that across samples, irradiation does notaffect phosphate binding. On accelerated storage stability testing formaterial of examples E4 to E24 there is a slight decrease in phosphatebinding however this is wholly consistent with the decline seen onstorage of the 2:1 ratio mixed metal compound, prepared according to themethod of WO 1999/015189. For samples E10 and E22, the change is smallat 6 kGy but is more pronounced at 8 kGy, therefore it is important toselect the lowest irradiation that maintains the preferredmicrobiological and physical stability. Phosphate binding offormulations E1 and E10 were not significantly reduced by the effect ofirradiation.

The initial E3 sample showed slightly high phosphate binding, this maybe due to sample heterogeneity (fast settling sample). The irradiatedand irradiated and accelerated storage stability tested sample displayedmore typical phosphate binding performance.

Hydrotalcite Structure of Mixed Metal Compound (XRD Analysis)

Diffraction Line Half Width of E1 and E10 were not significantlyinfluenced by irradiation and after storage stability testing treatment.

XRD's did not show any appearance of additional new crystalline phases(such as spinell) originating from a breakdown or change of thehydrotalcite structure when irradiated at the preferred radiationdosage.

Sterility (Microbiology)

From the microbiological data (Table 7) it is seen that a varyingquantity of irradiation is required to ensure sterility. For example,for formulation E22, the optimum irradiation dose is 8 kGy, whereas forformulation E24 the optimum irradiation dose is 6 kGy.

For formulation E1 the microbiological results showed that theformulation was not sterile post irradiation, the only way to make theformulation sterile would be to increase the irradiation dosage togreater than 10 kGy. It is very likely that this will further decreasethe physical properties of the formulation and exacerbate the separationproblem. Irradiation is therefore not considered a suitable method forpreserving this formulation. The total micro organism count for samplestested after manufacture was 680,000 cfu/1 ml of sample and was shown tospread post irradiation. All organisms were visually identified asBacillus spp (Predominant types: Gram negative bacilli). This indicatesthat irradiation of the formulation was not successful in the presenceof the silica.

For formulation E10 the total micro organism count for samples testedafter manufacture was 450,000 cfu/1 ml of sample. Post irradiationsamples were shown to be sterile i.e. zero organism count. All organismswere visually identified as Bacillus spp (Predominant types: Gramnegative bacilli). The microbiological results for formulation E10showed the formulation was sterile post irradiation.

No total micro organism count was performed on E3 samples taken postmanufacture; however the sample was shown to be sterile postirradiation.

Packaging

Suitable packaging forms may include sachets, bottles and food.

Thus an optimum combination of mixed metal compound, excipients andirradiation dose to produce efficacious, sterile formulation withacceptable formulation characteristics (palatability, grittiness) andpackaging (sachets and bottles) has been identified whilst maintaininggood P-binding (both initial and on storage), physical stability andmicrobiological count.

SUMMARY

The results clearly showed a decrease in the physical properties offormulations E1 and E10 both post irradiation and after storagestability testing. However, E10 was sterile whereas E1 was found not tobe.

Surprisingly, we found that to improve the stability of E10 it would befeasible to use a lower irradiation dose. A lower dose may stillpreserve the formulation but the irradiation would have a reduced effecton the physical properties of the formulation.

Formulation E3 was not physically stable, even prior to irradiation, andcould therefore not be assessed. This may have been a consequence oflimitations of the method of formulation make up.

Table 7 demonstrates that the preferred formulations which can besterilised are those that comprise combinations of xanthan gum with oneof PVP, LBG, methyl cellulose preferably selected from a preferred doserange. Although combinations of xanthan gum and colloidal silica orAvicel were found to prevent flocculation and sedimentation, uponirradiation, decomposition was observed.

4 kGy Irradiation Study

The composition of the formulations tested are given below.

Formulation 31 32 33 Raw Material % w/v % w/v % w/v Fermagate (MixedMetal Compound) 10 10 10 Sorbitol 70% solution 6 6 6 Xanthan gum 0.50.35 1.0 Methyl cellulose 0.5 — — Locust bean gum — 0.35 — PVP (KollidonCL M) — — 0.5

Each formulation was manufactured on a 3.5 litre scale and packed into125 ml translucent HDPE bottles.

The physical and chemical properties of each formulation were thentested at the following time points:—

-   1) Initial analysis after the manufacture of each batch.-   2) Post irradiation: All formulations were irradiated at an average    dose of 4 kGy; this was achieved by cycling between 3.6 and 4.4 kGy.

Four 125 ml bottles were available for testing at each stage ofanalysis.

Microbial analysis was performed by Isotron to determine bioburden countpre and post irradiation.

All 3 formulations were tested pre and post irradiation in respect of

-   -   appearance, pH and density    -   rheology (Method 15 and 16)    -   rotational viscosity (Method 17)    -   kinematic viscosity (Method 21)    -   centrifugal separation (Method 18)    -   gravitational separation (Method 22)    -   Microbiology (Method 12)

Results

Time point Test Units Initial Irradiated Appearance a a pH 9.2 9.0Density g/ml 1.08 1.11 Rotational viscosity cP 2706 1433 Kinematicviscosity seconds 32 13 Centrifugal separation % supernatant 0 0Gravimetric separation % supernatant 0 0 Elastic modulus G′ Pa 20.7 11.6Viscous modulus G″ Pa 7.7 5.8 Phase angle δ ° 20.3 26.4 Complexviscosity Pa · s 3.4 2.0 a = A rusty orange/brown colour with an aeratedtop layer.

Appearance, pH and Density Formulation 31

-   -   A rusty orange brown coloured suspension with an aerated top        layer after manufacture there was no change in appearance post        irradiation.    -   The pH was 9.2 at manufacture and 9.0 post irradiation.    -   The density was 1.08 g/ml at manufacture and 1.11 g/ml post        irradiation.

Formulation 32

-   -   A rusty orange brown coloured suspension after manufacture there        was no change in appearance post irradiation.    -   The pH was 9.2 at manufacture and 9.1 post irradiation.    -   The density was 1.12 g/ml at manufacture and 1.12 g/ml post        irradiation.

Formulation 33

-   -   A rusty orange brown coloured suspension after manufacture there        was no change in appearance post irradiation.    -   The pH was 9.2 at manufacture and 9.0 post irradiation.    -   The density was 1.12 g/ml at manufacture and 1.11 g/ml post        irradiation

Rheology Formulation 31

The Elastic modulus and the Viscous modulus were highest for initialsamples tested post manufacture; however they decreased followingirradiation. The phase angle increased from an initial value of 20.3° to26.4° post irradiation. This suggests the formulation became more liquidin behaviour following irradiation. A phase angle of greater than 45° isgenerally considered to be the transition between a gel and a liquid.

Formulation 32

The Elastic modulus and the Viscous modulus were highest for initialsamples tested post manufacture; however they decreased followingirradiation. The phase angle had a very small decrease from an initialvalue of 12.5° to 12.0° post irradiation. This suggests the irradiationhad very little effect on the gel properties of the formulation.

Formulation 33

The Elastic modulus was highest for initial samples tested postmanufacture; however decreased following irradiation. There was a verysmall increase in the Viscous modulus from manufacture to postirradiation. The phase angle increased from an initial value of 14.7° to24.0° post irradiation. This suggests the formulation became more liquidin behaviour following irradiation.

Rotational Viscosity Formulation 31

The initial rotational viscosity was 2706 cPs, this was reduced to 1433cPs after irradiation.

Formulation 32

The initial rotational viscosity was 5756 cPs, this was reduced to 4729cPs after irradiation.

Formulation 33

The initial rotational viscosity was 6256 cPs, this was reduced to 4136cPs after irradiation.

Kinematic Viscosity Formulation 31

The flow rate decreased from 32 seconds to 13 seconds for theformulation post irradiation for the first break in flow. At these timepoints 75 ml and 90 ml of sample had flowed through the orifice for postmanufacture and post irradiated samples respectively.

Formulation 32

No continuous flow was observed for the sample post manufacture or postirradiation.

The formulation formed droplets, the times given in the data tables isthe time for the first droplet to fall.

Formulation 33

The flow rate decreased from 22 seconds to 21 seconds for theformulation post irradiation. At these time points 45 ml and 73 ml ofsample had flowed through the orifice for post manufacture and postirradiated samples respectively.

Centrifugal Separation

For each of Formulations 31, 32 and 33 no separation occurred in samplestested immediately after manufacture and post irradiation.

Gravimetric Separation

For each of Formulations 31, 32 and 33 no separation occurred in samplestested immediately after manufacture and post irradiation.

Microbiology Formulation 31

The total micro organism count for samples tested after manufacture was6,600 cfu/ml of sample. Three of the five samples tested showed CFU's.The predominant types were visually identified as Bacillus spp andStaphylococcus spp. Post irradiation samples were shown to have 21cfu/ml of sample. One of the five samples tested showed CFU's. Thepredominant types were visually identified as Staphylococcus spp.

Formulation 32

The total micro organism count for samples tested after manufacture was30 cfu/ml of sample. One of the five samples tested showed CFU's. Thepredominant types were visually identified as Bacillus spp andStaphylococcus spp. Post irradiation samples were shown to have 0 cfu/mlof sample.

Formulation 33

The total micro organism count for samples tested after manufacture was20 cfu/ml of sample. One of the five samples tested showed CFU's. Thepredominant types were visually identified as Bacillus spp andStaphylococcus spp. Post irradiation samples were shown to have 0 cfu/mlof sample.

Conclusion Formulation 31

The results showed that following irradiation there was a change in therheological properties of the formulation indicating it had become moreliquid. This was consistent with what had been observed previously athigher irradiation doses; however, importantly these changes did notimpact on the suspending properties of formulation 31. The suspendingproperties of formulation 31 were unaffected by irradiation, as wereappearance, pH and density.

The microbiological results showed that the formulation was sterile postirradiation in four of the five samples tested.

Formulation 32

Formulation 2 was similar to Formulation 1 in that there were slightchanges to its rheological character post-irradiation; however, thesechanges did not alter the suspending properties.

The microbiological results showed that Formulation 2 was sterile postirradiation in all samples.

Formulation 33

Following irradiation, Formulation 3 behaved in a similar manner toFormulation 2. A dose of 4 kGy was sufficient to sterilise theformulation and, despite slight changes in rheological properties, itdid not separate and remained a physically stable suspension.

In summary, the irradiation of all tested formulations at 4 kGy resultedin a decrease in various rheological properties. This suggested theformulations became more liquid in character; however, despite thesechanges the suspending properties were unaffected at the current drugloading. Of the three formulations analysed, formulation 2 (xanthangum/locust bean gum) and formulation 3 (xanthan gum/PVP) were shown tobe sterile in all samples following irradiation at 4 kGy.

EXAMPLES

The mixed metal compound used in each of the examples of the presentspecification is Fermagate, available from INEOS Healthcare Ltd (UK).Fermagate is an iron magnesium hydroxy carbonate of the formula[Mg₄Fe₂(OH)₁₂].CO₃.4H₂O. The product is described in and may be preparedin accordance with the teachings of WO99/015189.

Formulation E1

To make 100 ml suspension:

To 6 g 70% sorbitol solution add 25 ml purified water. Whilst mixing,add 0.5 g colloidal silica and 10 g mixed metal compound. To this addsufficient water to make 50 ml suspension and mix well.

Warm (50° C.) 35 ml of water and whilst mixing add 0.5 g xanthan gum.Allow the solution to cool to room temperature and add sufficient waterto make 50 ml solution. Mix well.

Add the solution to the suspension and mix well.

Formulation E2

Using Lightin stirrer and 5 litre beaker

-   1. To 2250 ml purified water add 56.25 g Avicel RC 591.-   2. Mix to fully hydrate the Avicel-   3. Whilst mixing add 375 g mixed metal compound.-   4. Mix well-   5. To this add sufficient water to make 3750 ml suspension and mix    well.-   6. Pour into bucket.

Formulation E3

Using Lightin stirrer and 5 litre beaker

-   1. To 2250 ml purified water add 56.25 g Avicel RC 591.-   2. Mix to fully hydrate the Avicel-   3. Whilst mixing add 225 g 70% sorbitol solution followed by 375 g    mixed metal compound.-   4. Mix well-   5. To this add sufficient water to make 3750 ml suspension and mix    well.-   6. Pour into bucket.

Formulation E4

Using Lightin stirrer and 5 litre beaker

-   1. To 2250 ml purified water add 48.75 g Avicel RC 591.-   2. Mix to fully hydrate the Avicel (approx 30 mins)-   3. Add 11.25 g xanthan gum-   4. Mix for 16 minutes-   5. Whilst still mixing add 225 g 70% sorbitol solution followed by    375 g mixed metal compound.-   6. Mix well-   7. To this add sufficient water to make 3750 ml suspension and mix    well.-   8. Pour into bucket

Formulation E5

-   1. To 2250 ml purified water add 48.75 g Avicel CL 611-   2. Mix to fully hydrate the Avicel-   3. Add 11.25 g xanthan gum and mix to fully hydrate-   4. Add 0.75 g locust bean gum-   5. Whilst mixing add 225 g 70% sorbitol solution followed by 375 g    mixed metal compound.-   6. Mix well-   7. To this add sufficient water to make 3750 ml suspension and mix    well.-   8. Pour into bucket.

Formulation E10

Preparation of suspension

Use Kitchen aid mixer

-   1. To 450 g 70% sorbitol solution add 1875 ml purified water.-   2. Whilst mixing add 37.5 g methyl cellulose and 750 g mixed metal    compound.-   3. To this add sufficient water to make 3750 ml suspension and mix    well.

Preparation of solution Phase

Use Lightin stirrer

-   1. Warm (50° C.) 2625 ml of water-   2. Whilst mixing add 37.5 g xanthan gum mix well.-   3. Allow the solution to cool to room temperature-   4. Add sufficient water to make 3750 ml solution. Mix well.

Combination of Two Phases

-   1. Transfer solution phase into the suspension phase.-   2. Mix well-   3. Dispense into a labelled bottles.

Formulations E6 to E14

35 Formulations E6 to E14 were made in accordance with the method forE10 but with excipients in quantities described in Table 3.

Formulation E22

Preparation of suspension

Use Kitchen Aid mixer

-   1. To 1875 ml of purified water add 37.5 g Kollidon CLM.-   2. Whilst mixing add 450 g of 70% sorbitol solution and 750 g mixed    metal compound.-   3. To this add sufficient water to make 3750 ml suspension and mix    well.

Preparation of solution Phase

Use Lightin stirrer

-   1. Warm (50° C.) 2250 ml of water-   2. Whilst mixing add 75 g xanthan gum and mix well.-   3. Allow the solution to cool to room temperature-   4. Add sufficient water to make 3750 ml solution. Mix well.

Combination of Two Phases

-   1. Transfer suspension phase into the solution phase.-   2. Mix well-   3. Dispense into a labelled bottles.

Formulations E15 to E23

Were made in accordance with the method for E22 but with excipients inquantities described in Table 3.

Formulation E24

-   1. To 1100 ml purified water add 13.125 g xanthan gum and mix to    fully hydrate (=Phase A).-   2. In a separate beaker add 13.125 g Locust bean gum to 1100 ml    purified water and mix to fully hydrate (=Phase B).-   3. Add phase B to phase A and mix well.-   4. Add 225 g sorbitol solution followed by 375 g mixed metal    compound and mix well.-   5. To this add sufficient water to make 3750 ml suspension and mix    well.-   6. Pour into bucket

Formulations E25 to E30

were made in accordance with the method for E24 but with excipients inquantities described in Table 5.

Sachet Filling

Place a representative sample of the formulation into a sachet fillingmachine and pump the required quantity of sample into the selectedsachet. Agitation of the formulation batch may be required. Heat sealthe open end the sachet once filled.

Irradiation

Cobalt 60 is used as a source of gamma irradiation. The product to beirradiated are moved through the irradiation plant by a conveyor systemin such a way as to ensure uniform irradiation of the product at therequired irradiation intensity. In one particular irradiation system,the product can be placed inside a ‘tote box’ which is placed within theconveyor system. The absorption of irradiation by the product ismeasured indirectly using a dosimeter.

Methods Method 1—Particle Size Analysis Mixed Metal Compound

The particle size was determined using a Mastersizer ‘S’ fitted with a300Rf lens and a DIF 2012 dispersion unit. The data was interpreted andanalysed using Malvern Mastersizer software. The Malvern was connectedto a process grade water supply. The following program parameters wereused, 80% pump speed, 80% stirrer speed, 50% ultrasonic and 3 minuteresidence time. The background level was checked to be below 100 units.When prompted by the program the sample was added in portions to reachbetween 15%-25% obscuration. The analysis commenced automatically. Theresidual was checked to be less than 1%. The sample was analysed induplicate. The results were calculated using the software by taking the% volume under the particle sizes between 1.85 and 184 microns. This wasexpressed as percentile results with the Average Particle Size (D50,50^(th) percentile), 90^(th) Percentile (D90) and 10^(th) Percentile(D10).

Method 2—Calculation of Theoretical Fluid Yield Stress Required toSuspend Particle

For fluid systems containing particles, the yield stress of the fluidwhich is required to prevent sedimentation of those particles may bedetermined theoretically. The stress exerted by a spherical particle indilute suspension is calculated using the following formula:

σ_(s)=r g(d−ρ)/3

Therefore, if the fluid has a yield stress exceeding σ_(s) the suspendedparticles should in theory not settle out.

σ_(s)=yield stress, Par=particle radius, mg=acceleration due to gravity=9.81 m/s²d=particle density, kg/m³ρ=fluid density, kg/m³

Method 3—Yield Stress Measurement

The sample shear stress was characterised at varying levels of shearrate using a Physica (Anton Paar) Rheolab MC1, with Z1 bob and MB-Z1/SMcup. From the shear stress and shear rate data the yield stress can bereadily determined.

Method 4—Pourability

A qualitative assessment of the pourability (‘runny’, ‘thick’ etc.) ofthe liquid dose can be made by pouring the liquid from a suitablecontainer e.g. a transparent bottle.

Method 5—Gravimetric Settling Test

Approximately 45 ml sample is homogenised, placed in a straight sidedtransparent container of 50 ml volume. The volume of sediment orsupernatant is observed at specified time intervals and may be expressedas a % of the total sample volume.

Method 6—Accelerated Settling Test 1

A 40 ml sample was centrifuged using a Labofuge 400R centrifuge runningat 500 rpm for 15 minutes. The degree of separation was then quantifiedby calculating the volume of sediment or supernatant as a percentage ofthe total sample volume.

Method 7—Accelerated Settling Test 2

A 40 ml sample was centrifuged using a Labofuge 400R centrifuge runningat 2000 rpm for 15 minutes. The degree of separation was then quantifiedby calculating the volume of sediment or supernatant as a percentage ofthe total sample volume.

Method 8—Irradiation

500 ml sample stored in a plastic bottle was irradiated with gammaradiation at a dose level of between 6 and 10 kGy.

Method 9—Storage Stability Testing 1

500 ml of sample stored in a plastic bottle was placed in an oven at atemperature of 60° C. for one week. The sample was cooled to roomtemperature prior to testing.

Method 10—Storage Stability Testing 2

500 ml of sample stored in a plastic bottle was placed in an oven at atemperature of 50° C. for one week. The sample was cooled to roomtemperature prior to testing.

Method 11—pH

10 ml of sample was transferred to a sterilin jar and the pH measuredwhilst stirring using a calibrated pH meter.

Method 12—Microbiological Testing

The microbiological dose setting procedures, in accordance withrecognised standards (BS EN 552/ISO11137, ‘Sterilization of medicaldevices. Validation and routine control of sterilization byirradiation’) require exposure of product to low, predeterminedirradiation doses.

Method 13—Phosphate Binding

5 ml of sample was added to 7.5 ml of 67 mM phosphate solutionmaintained at 37° C., and agitated on an orbital shaker for 30 minutes.Slurry then filtered through 0.45 μm filter tip, and 1 ml of resultantfiltrate diluted to 100 ml with AnalaR water. This solution was analysedon UV/Vis spectrophotometer using molybdovanadic colorimetric method at375 nm.

Method 14—Diffraction Line Half Width

Liquid dose sample dried in an oven at 50° C. overnight. Dried samplemilled via pestle and mortar and approx 2 g sent to LGC Runcorn for fullscan powder x-ray diffraction. The powders were run as received in deeppacked specimen holders, and data collected from 2-70 degrees 2 theta ona Philips PW1800 automatic powder x-ray diffractometer using copper kalpha radiation generated at 40 kV and 55 mM and a 4 second per pointcount time.

Method 15—Yield Stress Measurement

The sample shear stress was characterised at varying levels of shearrate using a Bohlin CVO controlled stress rheometer using cone and plategeometry (CP 4°/40 mm) @ 25° C.

From the shear stress and shear rate data the yield stress can bereadily determined.

Method 16—Phase Angle Measurement

The phase angle characterised using a Bohlin CVO controlled stressrheometer using cone and plate geometry (CP 4°/40 mm) @ 25° C.

Method 17—Complex Viscosity

The complex viscosity was characterised using a Brookfield LVDV-II+viscometer, spindle 3 set at 12 rpm.

Method 18—Accelerated Separation Test 3

The sample was centrifuged using an accuSPIN 400 (Fisher) centrifugerunning at 1000 rpm for 10 minutes. The degree of separation was thenquantified by calculating the volume of sediment or supernatant as apercentage of the total sample volume.

Method 19—Phosphate Binding Test for Mixed Metal Compound PhosphateBinding Capacity and Mg Release

Phosphate buffer (pH=4) was prepared by weighing 5.520 g (+/−0.001 g) ofsodium di-hydrogen phosphate followed by addition of AnalaR™ water andtransferring to a 1 ltr volumetric flask.

To the 1 ltr volumetric flask was then added 1 M HCl drop-wise to adjustthe pH to pH 4 (+/−0.1) mixing between additions. The volume was thenaccurately made up to 1 ltr using AnalaR™ water and mixed thoroughly.

0.5 g (+/−0.005 g) of each sample was added to a volumetric flask (50ml) containing 40 mM phosphate buffer solution (12.5 ml) at 37.5° C. ina Grant OLS 200 Orbital shaker. All samples were prepared in duplicate.The vessels were agitated in the orbital shaker for 30 minutes. Thesolution was then filtered using a 0.45 μm syringe filter. 2.5 mlaliquots of supernatant were pipetted of the supernatant and transferredinto a fresh blood collection tubes. 7.5 ml of AnalaR™ water werepipetted to each 2.5 ml aliquot and the screw cap fitted and mixedthoroughly. The solutions were then analysed on a calibrated UV Vis.

The phosphate binding capacity was determined by:

Phosphate binding (mmol/g)=S _(P)(mmol/l)−T _(P)(mmol/l)/W(g/l)

where:T_(P)=Analyte value for phosphate in the phosphate solution afterreaction with phosphate binder=solution P (mg/l)*4/30.97.S_(P)=Analyte value for phosphate in the phosphate solution beforereaction with phosphate binder.W=concentration binder (g/l) used in test method (i.e. 0.4 g/10 ml=40g/l)Magnesium release was determined by:

Magnesium release (mmol/g)=T _(Mg)(mmol/l)−S _(Mg)(mmol/l)/W(g/l)

where:T_(Mg)=Analyte value for magnesium in the phosphate solution afterreaction with phosphate binder=solution Mg (mg/l)*4/24.31.S_(Mg)=Analyte value for magnesium in the phosphate solution beforereaction with phosphate binder.

Method 20—Particle Density

Particle density can be derived by measuring the volume of liquidrequired to fill the inter-particle space within a sample of mixed metalcompound of known mass and bulk volume. The particle volume iscalculated by subtracting the liquid volume from the bulk volume. Theparticle density is calculated by dividing the original sample mass bythe derived particle volume result. The mixed metal compound should bepoorly soluble in the selected liquid.

Method 21—Kinematic Viscosity

The kinematic viscosity was determined using a Ford ASTM D1200 cup No 5.This is designed for flow times between 30 and 100 seconds, by allowinga known volume (100 ml) to flow through an orifice of specificdimensions.

Method 22—Gravitational Separation

The gravitational separation was assessed by monitoring 10 ml of samplein a measuring cylinder over a period of time. Any phase separation wasnoted and the volume of supernatant recorded.

All publications mentioned in the above specification are hereinincorporated by reference. Various modifications and variations of thedescribed methods and system of the invention will be apparent to thoseskilled in the art without departing from the scope and spirit of theinvention. Although the invention has been described in connection withspecific preferred embodiments, it should be understood that theinvention as claimed should not be unduly limited to such specificembodiments. Indeed, various modifications of the described modes forcarrying out the invention which are obvious to those skilled inchemistry or related fields are intended to be within the scope of thefollowing claims

1.-24. (canceled)
 25. A method for binding phosphate comprisingadministering a composition comprising an aqueous suspension comprising:(i) an insoluble mixed metal compound capable of binding phosphatecontaining at least one trivalent metal selected from iron (III) andaluminium and at least one divalent metal selected from of magnesium,iron, zinc, calcium, lanthanum and cerium, wherein the component (i) ispresent in an amount up to 12% by weight, based on the total weight ofthe composition, (ii) xanthan gum present in the composition in anamount of no greater than about 2% by weight, based on the total weightof the composition; (iii) at least one of (a) polyvinyl pyrrolidone (b)locust bean gum (c) methyl cellulose wherein the composition has beenirradiated with ionising radiation in an amount of at least 4 kGy. 26.The method according to claim 25 where in the compound is of formula IM^(II) _(1-x)M^(III) _(x)(OH)₂A^(n−) _(y) .mH₂O  (I) wherein M^(II) isone or more bivalent metals and is at least Mg²⁺; M^(III) is one or moretrivalent metals and is at least Fe³⁺; A^(n−) is one or more n-valentanions and is at least CO₃ ²; (Σyn)/x is from 0.5 to 1.5 0<x≦0.4, 0<y≦1and 0<m≦10.
 27. The method according to claim 25 wherein the compoundhas an aluminium content of less than 10000 ppm.
 28. The methodaccording to claim 25 wherein the composition has been irradiated withionising radiation in an amount of at least 6 kGy.
 29. The methodaccording to claim 25 wherein the composition has been irradiated withionising radiation in an amount of at least 8 kGy.
 30. The methodaccording to claim 25 wherein the composition has been irradiated withionising radiation in an amount of at least 10 kGy.
 31. The methodaccording to claim 25 wherein component (iii) is present in an amount ofno greater than 2 wt % based on weight of the composition.
 32. Themethod according to claim 25 wherein the xanthan gum and component (iii)are present in a ratio of 2:1 to 1:2.
 33. The method according to claim25 wherein the xanthan gum and component (iii) are present in a ratio ofapproximately 1:1.
 34. The method according to claim 25 wherein thecomposition comprises at least polyvinyl pyrrolidone.
 35. The methodaccording to claim 34 wherein the composition comprises (ii) xanthan gumand (iii) polyvinyl pyrrolidone, wherein the xanthan gum and polyvinylpyrrolidone are present in a ratio of approximately 2:1.
 36. The methodaccording to claim 34 wherein the composition has been irradiated withionising radiation in an amount of at least 8 kGy.
 37. The methodaccording to claim 25 wherein the composition comprises at least locustbean gum.
 38. The method according to claim 37 wherein the compositioncomprises (ii) xanthan gum and (iii) locust bean gum, wherein thexanthan gum and locust bean gum are present in a ratio of approximately1:1.
 39. The method according to claim 37 wherein the composition hasbeen irradiated with ionising radiation in an amount of at least 6 kGy.40. The method according to claim 25 wherein the composition comprisesat least methyl cellulose.
 41. The method according to claim 40 whereinthe composition comprises (ii) xanthan gum and (iii) methyl cellulose,wherein the xanthan gum and methyl cellulose are present in a ratio ofapproximately 1:1.
 42. The method according to claim 40 wherein thecomposition has been irradiated with ionising radiation in an amount ofat least 10 kGy.
 43. The method according to claim 25 wherein thecomposition is a pharmaceutical composition and optionally furthercomprises (iv) one or more pharmaceutically acceptable adjuvants,excipients, diluents or carriers.
 46. The method according to claim 25,comprising administering the composition in amount effective for thetreatment of hyperphosphataemia.
 47. A method of binding phosphatecomprising administering a composition comprising an aqueous suspensioncomprising: (i) an insoluble mixed metal compound capable of bindingphosphate containing at least one trivalent metal selected from iron(iii) and aluminum and at least one divalent metal selected frommagnesium, iron, zinc, calcium, lanthanum, and cerium, wherein component(i) is present in the composition in an amount of about 8% to 12% byweight, based on the total weight of the composition, (ii) xanthan gum,wherein component (ii) is present in the composition in an amount of nogreater than about 2% by weight, based on the total weight of thecomposition, and (iii) at least one of (a) polyvinyl pyrrolidone, (b)locust bean gum, and (c) methyl cellulose, wherein component (iii) ispresent in an amount no greater than about 2% by weight based on thetotal weight of the composition, wherein the composition has beenirradiated with ionizing radiation in an amount of at least 4 kGy.
 48. Amethod for binding phosphate, comprising administering an aqueoussuspension comprising: (i) an insoluble mixed metal compound capable ofbinding phosphate containing at least one trivalent metal selected fromiron (III) and aluminium and at least one divalent metal selected frommagnesium, iron, zinc, calcium, lanthanum and cerium, (ii) xanthan gum;(iii) at least one of (a) polyvinyl pyrrolidone (b) locust bean gum (c)methyl cellulose wherein the xanthan gum and component (iii) areprovided in a ratio of 2:1 to 1:2, the suspension has been irradiatedwith ionising radiation in an amount of at least 4 kGy, and thesuspension has a yield stress of greater than about 2.6 Pa to about 19Pa.
 49. The method of claim 48, wherein the xanthan gum is present inthe suspension in an amount of no greater than about 2% by weight, basedon the total weight of the suspension.
 50. The method of claim 49,wherein the mixed metal compound is present in the suspension in anamount up to about 12 wt %.